Treatment of Mtres1 Related Diseases and Disorders

This application claims the benefit of U.S. Provisional Application No. 63/429,763, filed on Dec. 2, 2022, U.S. Provisional Application No. 63/432,854, filed on Dec. 15, 2022, U.S. Provisional Application No. 63/582,781, filed on Sep. 14, 2023, U.S. Provisional Application No. 63/540,624, filed on Sep. 26, 2023, which applications are incorporated herein by reference.

The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled 54462-743_601_SL.xml, created Nov. 30, 2023, which is 8,590,920 bytes in size. The information in the electronic format of the Sequence Listing is incorporated by reference in its entirety.

Neurological disorders are a common problem, particularly in the older population. Improved therapeutics are needed for treating these disorders.

4 30 In certain aspects, described herein is a composition comprising an oligonucleotide that targets MTRES1 and when administered to a subject in an effective amount decreases central nervous system (CNS) MTRES1, wherein the oligonucleotide comprises any one of SEQ ID NOS: 2675, 2677-2686, 2689, 2720, 2729, 2739, 2745, 2748, 2749, 2754, 2758-2762, 2766, 2767, 2769, 2770, 2786, 2787-2812, 2814-2816, 2819-2822, 2824, 2828-2833, 2836, 2838, 2839, 2857, 2859-2868, 2871, 2873, 2874, 2877-2879, 2940-2944, 2948-2952, 2968-2994, 2996-2998, 3001-3004, 3006, 3010, 3011, 3013-3015, 3018, or 3020. In some embodiments, the oligonucleotide comprises a modified internucleoside linkage. In some embodiments, the modified internucleoside linkage comprises alkylphosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof. In some embodiments, the modified internucleoside linkage comprises one or more phosphorothioate linkages. In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified internucleoside linkages. In some embodiments, the oligonucleotide comprises a modified nucleoside. In some embodiments, the modified nucleoside comprises a locked nucleic acid (LNA), hexitol nucleic acid (HNA), cyclohexene nucleic acid (CeNA), 2′-O-methoxyethyl, 2′-O-alkyl, 2′-O-allyl, 2′-O-allyl, 2′-fluoro, 2′-deoxy, or 2′-O-methyl inosine, or a combination thereof. In some embodiments, the modified nucleoside comprises an LNA. In some embodiments, the modified nucleoside comprises a 2′,4′ constrained ethyl nucleic acid. In some embodiments, the modified nucleoside comprises a 2′-O-methyl nucleoside, 2′-deoxyfluoro nucleoside, 2′-O—N-methylacetamido (2′-O-NMA) nucleoside, a 2′-O-dimethylaminoethoxyethyl(2′-O-DMAEOE) nucleoside, 2′-O-aminopropyl (2′-O-AP) nucleoside, or 2′-ara-F, or a combination thereof. In some embodiments, the modified nucleoside comprises one or more 2′-fluoro modified nucleosides. In some embodiments, the modified nucleoside comprises a 2′-O-alkyl modified nucleoside. In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 modified nucleosides. In some embodiments, the oligonucleotide comprises a lipophilic moiety attached at a 3′ or 5′ terminus of the oligonucleotide. In some embodiments, the lipophilic moiety comprises cholesterol, retinoic acid, cholic acid, adamantane acetic acid, 1-pyrene butyric acid, dihydrotestosterone, 1,3-bis-O(hexadecyl)glycerol, geranyloxyhexyanol, hexadecylglycerol, borneol, menthol, 1,3-propanediol, heptadecyl, palmitic acid, myristic acid, O3-(oleoyl) lithocholic acid, O3-(oleoyl) cholenic acid, ibuprofen, naproxen, dimethoxytrityl, or phenoxazine. In some embodiments, the lipophilic moiety comprises a C-Chydrocarbon chain. In some embodiments, the lipophilic moiety comprises a lipid. In some embodiments, the lipid comprises myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl stearyl, α-tocopherol, or a combination thereof. In some embodiments, the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand. In some embodiments, the sense strand is 12-30 nucleosides in length. In some embodiments, the antisense strand is 12-30 nucleosides in length.

In certain aspects, described herein is a composition comprising an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand is independently about 12-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 12-30 contiguous nucleosides of SEQ ID NOS: 2675, 2677-2686, 2689, 2720, 2729, 2739, 2745, 2748, 2749, 2754, 2758-2762, 2766, 2767, 2769, 2770, 2786, 2787-2812, 2814-2816, 2819-2822, 2824, 2828-2833, 2836, 2838, 2839, 2857, 2859-2868, 2871, 2873, 2874, 2877-2879, 2940-2944, 2948-2952, 2968-2994, 2996-2998, 3001-3004, 3006, 3010, 3011, 3013-3015, 3018, or 3020. In some embodiments, any one of the following is true with regard to the sense strand: all purines comprise 2′-fluoro modified purines, and all pyrimidines comprise a mixture of 2′-fluoro and 2′-methyl modified pyrimidines; all purines comprise 2′-methyl modified purines, and all pyrimidines comprise a mixture of 2′-fluoro and 2′-methyl modified pyrimidines; all purines comprise 2′-fluoro modified purines, and all pyrimidines comprise 2′-methyl modified pyrimidines; all pyrimidines comprise 2′-fluoro modified pyrimidines, and all purines comprise a mixture of 2′-fluoro and 2′-methyl modified purines; all pyrimidines comprise 2′-methyl modified pyrimidines, and all purines comprise a mixture of 2′-fluoro and 2′-methyl modified purines; or all pyrimidines comprise 2′-fluoro modified pyrimidines, and all purines comprise 2′-methyl modified purines. In some embodiments, any one of the following is true with regard to the sense strand: (a) all purines comprise 2′-fluoro modified purines and all pyrimidines comprise (i) a mixture of 2′-O-methyl and 2′-O-methoxyethyl modified pyrimidines; or (ii) a mixture of 2′-fluoro, 2′-O-methyl, and 2′-O-methoxyethyl modified pyrimidines; (b) all purines comprise 2′-O-methyl modified purines and all pyrimidines comprise (i) a mixture of 2′-fluoro and 2′-O-methoxyethyl modified pyrimidines; or (ii) a mixture of 2′-fluoro, 2′-O-methyl, and 2′-O-methoxyethyl modified pyrimidines; (c) all purines comprise 2′-O-methoxyethyl modified purines and all pyrimidines comprise (i) a mixture of 2′-fluoro and 2′-O-methyl modified pyrimidines; or (ii) a mixture of 2′-fluoro, 2′-O-methyl, and 2′-O-methoxyethyl modified pyrimidines; (d) all purines comprise a mixture of 2′-fluoro and 2′-O-methyl modified purines and all pyrimidines comprise (i) 2′-O-methoxyethyl modified pyrimidines; (ii) a mixture of 2′-O-methyl and 2′-O-methoxyethyl modified pyrimidines; (iii) a mixture of 2′-fluoro and 2′-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2′-fluoro, 2′-O-methyl, and 2′-O-methoxyethyl modified pyrimidines; (e) all purines comprise a mixture of 2′-fluoro and 2′-O-methoxyethyl modified purines and all pyrimidines comprise (i) 2′-O-methyl modified pyrimidines; (ii) a mixture of 2′-fluoro and 2′-O-methyl modified pyrimidines; (iii) a mixture of 2′-O-methyl and 2′-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2′-fluoro, 2′-O-methyl, and 2′-O-methoxyethyl modified pyrimidines; (f) all purines comprise a mixture of 2′-O-methyl and 2′-O-methoxyethyl modified purines and all pyrimidines comprise (i) 2′-fluoro modified pyrimidines; (ii) a mixture of 2′-fluoro and 2′-O-methyl modified pyrimidines; (iii) a mixture of 2′-fluoro and 2′-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2′-fluoro, 2′-O-methyl, and 2′-O-methoxyethyl modified pyrimidines; or (g) all purines comprise a mixture of 2′-fluoro, 2′-O-methyl, and 2′-O-methoxyethyl modified purines and all pyrimidines comprise (i) 2′-fluoro modified pyrimidines; (ii) 2′-O-methyl modified pyrimidines; (iii) 2′-O-methoxyethyl modified pyrimidines; (iv) a mixture of 2′-fluoro and 2′-O-methyl modified pyrimidines; (v) a mixture of 2′-O-methyl and 2′-O-methoxyethyl modified pyrimidines; (vi) a mixture of 2′-fluoro and 2′-O-methoxyethyl modified pyrimidines; or (vii) a mixture of 2′-fluoro, 2′-O-methyl, and 2′-O-methoxyethyl modified pyrimidines; and with the proviso that in any of the foregoing, the sense strand may include a 2′-deoxy nucleoside. In some embodiments, any one of the following is true with regard to the antisense strand: all purines comprise 2′-fluoro modified purines, and all pyrimidines comprise a mixture of 2′-fluoro and 2′-methyl modified pyrimidines; all purines comprise 2′-methyl modified purines, and all pyrimidines comprise a mixture of 2′-fluoro and 2′-methyl modified pyrimidines; all purines comprise 2′-methyl modified purines, and all pyrimidines comprise 2′-fluoro modified pyrimidines; all pyrimidines comprise 2′-fluoro modified pyrimidines, and all purines comprise a mixture of 2′-fluoro and 2′-methyl modified purines; all pyrimidines comprise 2′-methyl modified pyrimidines, and all purines comprise a mixture of 2′-fluoro and 2′-methyl modified purines; or all pyrimidines comprise 2′-methyl modified pyrimidines, and all purines comprise 2′-fluoro modified purines. In some embodiments, the oligonucleotide comprises a phosphate at the 5′ end of the antisense strand. In some embodiments, the oligonucleotide comprises a phosphate mimic at the 5′ end of the antisense strand. In some embodiments, the phosphate mimic comprises a 5′-vinyl phosphonate (VP). In some embodiments, the oligonucleotide comprises an antisense oligonucleotide (ASO). In some embodiments, the ASO is 12-30 nucleosides in length.

In certain aspects, described herein is a composition comprising: a small interfering RNA (siRNA) comprising a sense strand, an antisense strand complementary to a section of an MTRES1 mRNA, and a lipid moiety connected to an end of the sense or antisense strand; wherein the lipid moiety comprises (a) a phenyl or cyclohexanyl linker, and (b) a lipid, wherein the linker is connected to the lipid and to the end of the sense or antisense strand. In some embodiments, the lipid and the end of the sense or antisense strand are connected to the phenyl or cyclohexanyl linker in the 1,4; 1,3; or 1,2 substitution pattern. In some embodiments, the lipid and the end of the sense or antisense strand are connected to the phenyl or cyclohexanyl linker in the 1,4-substitution pattern. In some embodiments, the lipid moiety comprises the following structure:

wherein the dotted line indicates a covalent connection to the end of the sense or antisense strand, with the proviso that R is not an octane. In some embodiments, the lipid moiety comprises the following structure:

wherein the dotted line indicates a covalent connection to the end of the sense or antisense strand, n is 1-3, and R is an alkyl group containing 4-18 carbons. In some embodiments, the lipid moiety comprises the following structure:

wherein the dotted line indicates a covalent connection to the end of the sense or antisense strand, n is 0-3, and R is an alkyl group containing 4-18 carbons. In some embodiments, the lipid moiety comprises the following structure:

wherein the dotted line indicates a covalent connection to the end of the sense or antisense strand. In some embodiments, the lipid moiety comprises a lipid moiety depicted in Table 1.

In certain aspects, described herein is a composition comprising an siRNA that targets MTRES1 and when administered to a cell modulates the expression of MTRES1, wherein the siRNA comprises a sense strand and an antisense strand; and wherein the sense strand or the antisense strand comprises any of modification patterns 33S to 65S or 11AS to 40AS. In some embodiments, the oligonucleotide comprises any one of SEQ ID NOS: 1-2280, 2550-3037, 3263-3266, 3281-3295, or 3338. In some embodiments, the oligonucleotide comprises any one of SEQ ID NOS: 2675, 2677-2686, 2689, 2720, 2729, 2739, 2745, 2748, 2749, 2754, 2758-2762, 2766, 2767, 2769, 2770, 2786, 2787-2812, 2814-2816, 2819-2822, 2824, 2828-2833, 2836, 2838, 2839, 2857, 2859-2868, 2871, 2873, 2874, 2877-2879, 2940-2944, 2948-2952, 2968-2994, 2996-2998, 3001-3004, 3006, 3010, 3011, 3013-3015, 3018, or 3020.

In certain aspects, described herein is a composition comprising an siRNA that targets MTRES1 and when administered to a cell modulates the expression of MTRES1, wherein the siRNA comprises a sense strand and an antisense strand; and wherein the sense strand comprises any one of SEQ ID NOs: 3038-3124, 3239, 3241-3242, 3259-3260, 3267-3273, 3296-3299, or 3305-3318 or the antisense strand comprises any one of SEQ ID NOs: 3125-3212, 3243-3250, 3261-3262, 3274-3280, 3300-3304, or 3319-3337. In some embodiments, the method further comprises a pharmaceutically acceptable carrier. In some embodiments, the composition is formulated for administration to a central nervous system. In some embodiments, the composition is formulated for delivery to a neural cell. In some embodiments, described herein is a method of treating a subject having a neurological disorder, the method comprising administering an effective amount of the composition described herein to the subject. In some embodiments, the composition is administered intrathecally. In some embodiments, described herein is a method of treating a subject having a neurological disorder or who is at risk for developing the neurological disorder, the method comprising evaluating a subject's risk for developing a neurological disorder and administering an effective amount of the composition described herein to the subject. In some embodiments, the subject has a genotype at risk for developing Alzheimer's disease or dementia. In some embodiments, the subject is a heterozygous or homozygous carrier of APOE4. In some embodiments, the subject is a heterozygous or homozygous carrier of MTRES1 rs117058816-G (c.3+1G). In some embodiments, evaluating a subject's risk for developing a neurological disorder comprises calculating a polygenic risk score for developing Alzheimer's disease or dementia. In some embodiments, the subject has a polygenic risk score in the 40th percentile or higher, which is indicative of a high risk for developing Alzheimer's disease or dementia. In some embodiments, the subject has a polygenic risk score in the 20th percentile or higher, which is indicative of a high risk for developing Alzheimer's disease or dementia. In some embodiments, calculating a polygenic risk score comprises providing genomic data comprising one or more genotypes of the subject, wherein the one or more genotypes is associated with a high risk for developing Alzheimer's disease or dementia.

Large-scale human genetic data can improve the success rate of pharmaceutical discovery and development. A Genome Wide Association Study (GWAS) may detect associations between genetic variants and traits in a population sample. A GWAS may enable better understanding of the biology of disease and provide applicable treatments. A GWAS can utilize genotyping and/or sequencing data, and often involves an evaluation of millions of genetic variants that are relatively evenly distributed across the genome. The most common GWAS design is the case-control study, which involves comparing variant frequencies in cases versus controls. If a variant has a significantly different frequency in cases versus controls, that variant is said to be associated with disease. Association statistics that may be used in a GWAS are p-values, as a measure of statistical significance; odds ratios (OR), as a measure of effect size; or beta coefficients (beta), as a measure of effect size. Researchers often assume an additive genetic model and calculate an allelic odds ratio, which is the increased (or decreased) risk of disease conferred by each additional copy of an allele (compared to carrying no copies of that allele). An additional concept in design and interpretation of GWAS is that of linkage disequilibrium, which is the non-random association of alleles. The presence of linkage disequilibrium can obfuscate which variant is “causal.”

Functional annotation of variants and/or wet lab experimentation can identify the causal genetic variant identified via GWAS, and in many cases may lead to the identification of disease-causing genes. In particular, understanding the functional effect of a causal genetic variant (for example, loss of protein function, gain of protein function, increase in gene expression, or decrease in gene expression) may allow that variant to be used as a proxy for therapeutic modulation of the target gene, or to gain insight into potential therapeutic efficacy and safety of a therapeutic that modulates that target.

Identification of such gene-disease associations has provided insights into disease biology and may be used to identify novel therapeutic targets for the pharmaceutical industry. In order to translate the therapeutic insights derived from human genetics, disease biology in patients may be exogenously ‘programmed’ into replicating the observation from human genetics. There are several potential options for therapeutic modalities that may be brought to bear in translating therapeutic targets identified via human genetics into novel medicines. These may include well established therapeutic modalities such as small molecules and monoclonal antibodies, maturing modalities such as oligonucleotides, and emerging modalities such as gene therapy and gene editing. The choice of therapeutic modality can depend on several factors including the location of a target (for example, intracellular, extracellular, or secreted), a relevant tissue (for example, brain) and a relevant indication.

The MTRES1 gene is located on chromosome 6 and encodes mitochondrial transcription rescue factor 1 (MTRES1), also known as chromosome 6 open reading frame 203 (C6orf203). The MTRES1 gene may also be referred to as the C6orf203 gene. MTRES1 may include 240 amino acids. MTRES1 may include 245 amino acids. MTRES1 may be expressed in neural cells. MTRES1 may be cytoplasmic or intracellular. MTRES1 may be localized in mitochondria within the cell. MTRES1 may be involved in mitochondrial transcription regulation. MTRES1 may be involved in mitochondrial translation regulation. An example of a MTRES1 amino acid sequence, and further description of MTRES1 is included at uniprot.org under accession no. Q9POP8 (last modified Oct. 1, 2000).

MTRES1 RNA expression is often higher in mitochondria-rich tissues such as skeletal muscle, heart, liver, kidney, adrenal cortex, and brain. MTRES1 RNA may be expressed throughout the brain, with an average expression of 24 nTPM across all regions. Expression is generally higher within the cerebral cortex (nTPM=35.7), with highest expression within int prefrontal cortex. Within the prefrontal cortex, highest expression may be in the dorsomedial and dorsolateral regions. MTRES1 protein may also be detectable in the cortex, cerebellum, hippocampus and caudate, particularly within neuronal cells. Within neuronal cells, MTRES1 was found to have the highest levels of expression in astrocytes, neurons, and oligodendrocytes, with lower but measurable expression in microglia, endothelial cells, and fetal astrocytes.

Here it is shown that loss-of-function MTRES1 variants may protect against neurological diseases. For example, a loss-of-function MTRES1 variant was associated with protective associations against Alzheimer's disease, family history of Alzheimer's disease, dementia, vascular dementia, anticholinesterase medication use, and delirium. Therefore, inhibition of MTRES1 may serve as a therapeutic for treatment of a neurological disorder such as dementia, Alzheimer's disease, delirium, cognitive decline, vascular dementia, or Parkinson's disease.

Disclosed herein are compositions comprising an oligonucleotide that targets MTRES1. Where inhibition or targeting of MTRES1 is disclosed, it is contemplated that some embodiments may include inhibiting or targeting a MTRES1 protein or MTRES1 RNA. For example, by inhibiting or targeting an RNA (e.g. mRNA) encoded by the MTRES1 gene using an oligonucleotide described herein, the MTRES1 protein may be inhibited or targeted as a result of there being less production of the MTRES1 protein by translation of the MTRES1 RNA; or a MTRES1 protein may be targeted or inhibited by an oligonucleotide that binds or interacts with a MTRES1 RNA and reduces production of the MTRES1 protein from the MTRES1 RNA. Thus, targeting MTRES1 may refer to binding a MTRES1 RNA and reducing MTRES1 RNA or protein levels. The oligonucleotide may include a small interfering RNA (siRNA) or an antisense oligonucleotide (ASO). Also provided herein are methods of treating a neurological disorder by providing an oligonucleotide that targets MTRES1 to a subject in need thereof.

In some embodiments, the siRNAs described herein comprise a sense strand and an antisense strand. In some embodiments, the sense strand comprises any one of SEQ ID NOs: 3038-3124, 3239, 3241-3242, 3259-3260, 3267-3273, 3296-3299, or 3305-3318 or the antisense strand comprises any one of SEQ ID NOs: 3125-3212, 3243-3250, 3261-3262, 3274-3280, 3300-3304, or 3319-3337. In some embodiments, the sense strand or the antisense strand comprise any one of SEQ ID NOS: 2675, 2677-2686, 2689, 2720, 2729, 2739, 2745, 2748, 2749, 2754, 2758-2762, 2766, 2767, 2769, 2770, 2786, 2787-2812, 2814-2816, 2819-2822, 2824, 2828-2833, 2836, 2838, 2839, 2857, 2859-2868, 2871, 2873, 2874, 2877-2879, 2940-2944, 2948-2952, 2968-2994, 2996-2998, 3001-3004, 3006, 3010, 3011, 3013-3015, 3018, or 3020. In some embodiments, the sense strand or the antisense strand comprises any of modification patterns 33S to 65S or 11AS to 39AS.

th th In certain aspects, disclosed herein is a method of treating a subject having a neurological disorder, comprising administering an effective amount of the siRNAs disclosed herein to the subject. In some embodiments, disclosed herein is a method of treating a subject having a neurological disorder or who is at risk for developing the neurological disorder, the method comprising evaluating a subject's risk for developing a neurological disorder and administering an effective amount of the siRNAs disclosed herein to the subject. In some embodiments, the subject has a genotype at risk for developing Alzheimer's disease or dementia. In some embodiments, the subject is a heterozygous or homozygous carrier of APOE4. In some embodiments, the subject is a heterozygous or homozygous carrier of MTRES1 rs117058816-G (c.3+1G). In some embodiments, evaluating a subject's risk for developing a neurological disorder comprises calculating a polygenic risk score for developing Alzheimer's disease or dementia. In some embodiments, the subject has a polygenic risk score in the 40percentile or higher, which is indicative of a high risk for developing Alzheimer's disease or dementia. In some embodiments, the subject has a polygenic risk score in the 20percentile or higher, which is indicative of a high risk for developing Alzheimer's disease or dementia. In some embodiments, calculating a polygenic risk score comprises providing genomic data comprising one or more genotypes of the subject, wherein the one or more genotypes is associated with a high risk for developing Alzheimer's disease or dementia.

Disclosed herein, in some embodiments, are compositions comprising an oligonucleotide. In some embodiments, the composition comprises an oligonucleotide that targets MTRES1. In some embodiments, the composition consists of an oligonucleotide that targets MTRES1. In some embodiments, the oligonucleotide reduces MTRES1 mRNA expression in the subject. In some embodiments, the oligonucleotide reduces MTRES1 protein expression in the subject. The oligonucleotide may include a small interfering RNA (siRNA) described herein. The oligonucleotide may include an antisense oligonucleotide (ASO) described herein. In some embodiments, a composition described herein is used in a method of treating a disorder in a subject in need thereof. Some embodiments relate to a composition comprising an oligonucleotide for use in a method of treating a disorder as described herein. Some embodiments relate to use of a composition comprising an oligonucleotide, in a method of treating a disorder as described herein. In some embodiments, an oligonucleotide modulates MTRES1 mRNA or protein levels.

Some embodiments include a composition comprising an oligonucleotide that targets MTRES1 and when administered to a subject in an effective amount decreases MTRES1 mRNA or protein levels in a cell, fluid or tissue. In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 and when administered to a subject in an effective amount decreases MTRES1 mRNA levels in a cell or tissue. In some embodiments, the cell is a neural cell such as a central nervous system (CNS) cell. Some examples of CNS cells include neurons, glia, microglia, astrocytes, or oligodendrocytes. In some embodiments, the tissue is CNS or brain tissue. In some embodiments, the MTRES1 mRNA levels are decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the MTRES1 mRNA levels are decreased by about 10% or more, as compared to prior to administration. In some embodiments, the MTRES1 mRNA levels are decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the MTRES1 mRNA levels are decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the MTRES1 mRNA levels are decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the MTRES1 mRNA levels are decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the MTRES1 mRNA levels are decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.

In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 and when administered to a subject in an effective amount decreases MTRES1 protein levels in a cell, fluid or tissue. In some embodiments, the cell is a neural cell such as a central nervous system (CNS) cell. Some examples of CNS cells include neurons, glia, microglia, astrocytes, or oligodendrocytes. In some embodiments, the tissue is CNS or brain tissue. In some embodiments, the MTRES1 protein levels are decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the MTRES1 protein levels are decreased by about 10% or more, as compared to prior to administration. In some embodiments, the MTRES1 protein levels are decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the MTRES1 protein levels are decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the MTRES1 protein levels are decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the MTRES1 protein levels are decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the MTRES1 protein levels are decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.

In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 and when administered to a subject in an effective amount diminishes a neurological disorder phenotype. The neurological disorder disease may include dementia, Alzheimer's disease, delirium, cognitive decline, vascular dementia, or Parkinson's disease. In some embodiments, the neurological disorder phenotype is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the neurological disorder phenotype is decreased by about 10% or more, as compared to prior to administration. In some embodiments, the neurological disorder phenotype is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the neurological disorder phenotype is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the neurological disorder phenotype is decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the neurological disorder phenotype is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the neurological disorder phenotype is decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.

In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 and when administered to a subject in an effective amount enhances a protective phenotype against a neurological disorder in the subject. The neurological disorder may include dementia, Alzheimer's disease, delirium, cognitive decline, vascular dementia, or Parkinson's disease. In some embodiments, the protective phenotype is increased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the protective phenotype is increased by about 10% or more, as compared to prior to administration. In some embodiments, the protective phenotype is increased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to prior to administration. In some embodiments, the protective phenotype is increased by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the protective phenotype is increased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the protective phenotype is increased by no more than about 10%, as compared to prior to administration. In some embodiments, the protective phenotype is increased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the protective phenotype is increased by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the protective phenotype is increased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages.

In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 and when administered to a subject in an effective amount decreases a marker of neurodegeneration in the subject. Some example markers of neurodegeneration may include central nervous system (CNS) amyloid plaques, CNS tau accumulation, cerebrospinal fluid (CSF) beta-amyloid 42, CSF tau, CSF phospho-tau, CSF or plasma neurofilament light chain (NfL), Lewy bodies, or CSF alpha-synuclein. In some embodiments, the marker of neurodegeneration is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the marker of neurodegeneration is decreased by about 10% or more, as compared to prior to administration. In some embodiments, the marker of neurodegeneration is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the marker of neurodegeneration is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the marker of neurodegeneration is decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the marker of neurodegeneration is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the marker of neurodegeneration is decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.

In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 and when administered to a subject in an effective amount decreases central nervous system (CNS) amyloid plaques in the subject. In some embodiments, the CNS amyloid plaques are decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the CNS amyloid plaques are decreased by about 10% or more, as compared to prior to administration. In some embodiments, the CNS amyloid plaques are decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the CNS amyloid plaques are decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the CNS amyloid plaques are decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the CNS amyloid plaques are decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the CNS amyloid plaques are decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.

In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 and when administered to a subject in an effective amount decreases central nervous system (CNS) tau accumulation in the subject. In some embodiments, the CNS tau accumulation is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the CNS tau accumulation is decreased by about 10% or more, as compared to prior to administration. In some embodiments, the CNS tau accumulation is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the CNS tau accumulation is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the CNS tau accumulation is decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the CNS tau accumulation is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the CNS tau accumulation is decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.

In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 and when administered to a subject in an effective amount decreases cerebrospinal fluid (CSF) beta-amyloid 42 in the subject. In some embodiments, the CSF beta-amyloid 42 is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the CSF beta-amyloid 42 is decreased by about 10% or more, as compared to prior to administration. In some embodiments, the CSF beta-amyloid 42 is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the CSF beta-amyloid 42 is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the CSF beta-amyloid 42 is decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the CSF beta-amyloid 42 is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the CSF beta-amyloid 42 is decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.

In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 and when administered to a subject in an effective amount decreases cerebrospinal fluid (CSF) tau in the subject. In some embodiments, the CSF tau is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the CSF tau is decreased by about 10% or more, as compared to prior to administration. In some embodiments, the CSF tau is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the CSF tau is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the CSF tau is decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the CSF tau is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the CSF tau is decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.

In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 and when administered to a subject in an effective amount decreases cerebrospinal fluid (CSF) tau in the subject. In some embodiments, the CSF phospho-tau is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the CSF phospho-tau is decreased by about 10% or more, as compared to prior to administration. In some embodiments, the CSF phospho-tau is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the CSF phospho-tau is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the CSF phospho-tau is decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the CSF phospho-tau is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the CSF phospho-tau is decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.

In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 and when administered to a subject in an effective amount decreases cerebrospinal fluid (CSF) alpha-synuclein in the subject. In some embodiments, the CSF alpha-synuclein is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the CSF alpha-synuclein is decreased by about 10% or more, as compared to prior to administration. In some embodiments, the CSF alpha-synuclein is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the CSF alpha-synuclein is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the CSF alpha-synuclein is decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the CSF alpha-synuclein is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the CSF alpha-synuclein is decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.

In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 and when administered to a subject in an effective amount decreases Lewy bodies in the subject. In some embodiments, the Lewy bodies are decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the Lewy bodies are decreased by about 10% or more, as compared to prior to administration. In some embodiments, the Lewy bodies are decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the Lewy bodies are decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the Lewy bodies are decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the Lewy bodies are decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the Lewy bodies are decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.

In some embodiments, the composition comprises an oligonucleotide that targets MTRES1 and when administered to a subject in an effective amount increases cognitive function. In some embodiments, the cognitive function is increased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the cognitive function is increased by about 10% or more, as compared to prior to administration. In some embodiments, the cognitive function is increased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to prior to administration. In some embodiments, the cognitive function is increased by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the cognitive function is increased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the cognitive function is increased by no more than about 10%, as compared to prior to administration. In some embodiments, the cognitive function is increased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the cognitive function is increased by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the cognitive function is increased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages.

A. siRNAs

In some embodiments, the composition comprises an oligonucleotide that targets MTRES1, wherein the oligonucleotide comprises a small interfering RNA (siRNA). In some embodiments, the composition comprises an oligonucleotide that targets MTRES1, wherein the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand.

In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand is 12-30 nucleosides in length. In some embodiments, the composition comprises a sense strand that is 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleosides in length, or a range defined by any of the two aforementioned numbers. The sense strand may be 14-30 nucleosides in length. In some embodiments, the composition comprises an antisense strand is 12-30 nucleosides in length. In some embodiments, the composition comprises an antisense strand that is 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleosides in length, or a range defined by any of the two aforementioned numbers. The antisense strand may be 14-30 nucleosides in length.

In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand is independently about 12-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 12-30 contiguous nucleosides of a full-length human MTRES1 mRNA sequence such as SEQ ID NO: 2443. In some embodiments, at least one of the sense strand and the antisense strand comprise a nucleoside sequence comprising at least about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more contiguous nucleosides of one of SEQ ID NO: 2443.

In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand is independently about 12-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 12-30 contiguous nucleosides of a full-length human MTRES1 mRNA sequence such as SEQ ID NO: 2462. In some embodiments, at least one of the sense strand and the antisense strand comprise a nucleoside sequence comprising at least about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more contiguous nucleosides of one of SEQ ID NO: 2462.

In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a double-stranded RNA duplex. In some embodiments, the first base pair of the double-stranded RNA duplex is an AU base pair.

In some embodiments, the sense strand further comprises a 3′ overhang. In some embodiments, the 3′ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3′ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3′ overhang comprises 2 nucleosides. In some embodiments, the sense strand further comprises a 5′ overhang. In some embodiments, the 5′ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5′ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5′ overhang comprises 2 nucleosides.

In some embodiments, the antisense strand further comprises a 3′ overhang. In some embodiments, the 3′ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3′ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3′ overhang comprises 2 nucleosides. In some embodiments, the antisense strand further comprises a 5′ overhang. In some embodiments, the 5′ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5′ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5′ overhang comprises 2 nucleosides.

In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the siRNA binds with a 19mer in a human MTRES1 mRNA. In some embodiments, the siRNA binds with a 12mer, a 13mer, a 14mer, a 15mer, a 16mer, a 17mer, a 18mer, a 19mer, a 20mer, a 21mer, a 22mer, a 23mer, a 24mer, or a 25mer in a human MTRES1 mRNA.

In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the siRNA binds with a 17mer in a non-human primate MTRES1 mRNA. In some embodiments, the siRNA binds with a 12mer, a 13mer, a 14mer, a 15mer, a 16mer, a 17mer, a 18mer, a 19mer, a 20mer, a 21mer, a 22mer, a 23mer, a 24mer, or a 25mer in a non-human primate MTRES1 mRNA.

In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the siRNA binds with a human MTRES1 mRNA and less than or equal to 20 human off-targets, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human MTRES1 mRNA and less than or equal to 10 human off-targets, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human MTRES1 mRNA and less than or equal to 30 human off-targets, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human MTRES1 mRNA and less than or equal to 40 human off-targets, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human MTRES1 mRNA and less than or equal to 50 human off-targets, with no more than 2 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human MTRES1 mRNA and less than or equal to 10 human off-targets, with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human MTRES1 mRNA and less than or equal to 20 human off-targets, with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human MTRES1 mRNA and less than or equal to 30 human off-targets, with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human MTRES1 mRNA and less than or equal to 40 human off-targets, with no more than 3 mismatches in the antisense strand. In some embodiments, the siRNA binds with a human MTRES1 mRNA and less than or equal to 50 human off-targets, with no more than 3 mismatches in the antisense strand.

In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, siRNA binds with a human MTRES1 mRNA target site that does not harbor an SNP, with a minor allele frequency (MAF) greater or equal to 1% (pos. 2-18). In some embodiments, the MAF is greater or equal to about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20%.

In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1140, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1140, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand further comprises a 3′ overhang. In some embodiments, the 3′ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3′ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3′ overhang comprises 2 nucleosides. In some embodiments, the sense strand further comprises a 5′ overhang. In some embodiments, the 5′ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5′ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5′ overhang comprises 2 nucleosides. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1140, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3′ end. In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1-1140.

In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1141-2280, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1141-2280, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand further comprises a 3′ overhang. In some embodiments, the 3′ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3′ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3′ overhang comprises 2 nucleosides. In some embodiments, the antisense strand further comprises a 5′ overhang. In some embodiments, the 5′ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5′ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5′ overhang comprises 2 nucleosides. In some embodiments, the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1141-2280, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3′ end. In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 1141-2280.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in any one of Tables 3-8, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in any one of Tables 3-8, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in any one of Tables 3-8. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) MTRES1 mRNA. The siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 12B, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 12B, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 12B. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) MTRES1 mRNA. The siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. The siRNA may include a moiety such as a lipid moiety or a GalNAc moiety.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 14B, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 14B, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 14B. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) MTRES1 mRNA. The siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. The siRNA may include a moiety such as a lipid moiety or a GalNAc moiety.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 16B, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 16B, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 16B. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) MTRES1 mRNA. The siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. The siRNA may include a moiety such as a lipid moiety or a GalNAc moiety.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 52B, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 52B, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 52B. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) MTRES1 mRNA. The siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. The siRNA may include a moiety such as a lipid moiety or a GalNAc moiety.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 54B, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 54B, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 54B. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) MTRES1 mRNA. The siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. The siRNA may include a moiety such as a lipid moiety or a GalNAc moiety.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 57, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 57, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 57. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) MTRES1 mRNA. The siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. The siRNA may include a moiety such as a lipid moiety or a GalNAc moiety.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 60, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 60, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 60. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) MTRES1 mRNA. The siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. The siRNA may include a moiety such as a lipid moiety or a GalNAc moiety.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 62B, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 62B, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 62B. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) MTRES1 mRNA. The siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. The siRNA may include a moiety such as a lipid moiety or a GalNAc moiety.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 64B, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 64B, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 64B. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) MTRES1 mRNA. The siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. The siRNA may include a moiety such as a lipid moiety or a GalNAc moiety.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 67B, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 67B, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 67B. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) MTRES1 mRNA. The siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. The siRNA may include a moiety such as a lipid moiety or a GalNAc moiety.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 69, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 69, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 69. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) MTRES1 mRNA. The siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. The siRNA may include a moiety such as a lipid moiety or a GalNAc moiety.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 72, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 72, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 72. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) MTRES1 mRNA. The siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. The siRNA may include a moiety such as a lipid moiety or a GalNAc moiety.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 75, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 75, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 75. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) MTRES1 mRNA. The siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. The siRNA may include a moiety such as a lipid moiety or a GalNAc moiety.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 78, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 78, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 78. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) MTRES1 mRNA. The siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. The siRNA may include a moiety such as a lipid moiety or a GalNAc moiety.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 81, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 81, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 81. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) MTRES1 mRNA. The siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. The siRNA may include a moiety such as a lipid moiety or a GalNAc moiety.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 84, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 84, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 84. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) MTRES1 mRNA. The siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. The siRNA may include a moiety such as a lipid moiety or a GalNAc moiety.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 87, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 87, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 87. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) MTRES1 mRNA. The siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. The siRNA may include a moiety such as a lipid moiety or a GalNAc moiety.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 90, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 90, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 90. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) MTRES1 mRNA. The siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. The siRNA may include a moiety such as a lipid moiety or a GalNAc moiety.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 93, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 93, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 93. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) MTRES1 mRNA. The siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. The siRNA may include a moiety such as a lipid moiety or a GalNAc moiety.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 96, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 96, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 96. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) MTRES1 mRNA. The siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. The siRNA may include a moiety such as a lipid moiety or a GalNAc moiety.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 98, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 98, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 98. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) MTRES1 mRNA. The siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications. The siRNA may include a moiety such as a lipid moiety or a GalNAc moiety.

In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 2674-2855, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 2674-2855, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand further comprises a 3′ overhang. In some embodiments, the 3′ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3′ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3′ overhang comprises 2 nucleosides. In some embodiments, the sense strand further comprises a 5′ overhang. In some embodiments, the 5′ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5′ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5′ overhang comprises 2 nucleosides. In some embodiments, the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 2674-2855, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3′ end. In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 2674-2855.

In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 2856-3037, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 2856-3037, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand further comprises a 3′ overhang. In some embodiments, the 3′ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 3′ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 3′ overhang comprises 2 nucleosides. In some embodiments, the antisense strand further comprises a 5′ overhang. In some embodiments, the 5′ overhang comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the aforementioned numbers. In some embodiments, the 5′ overhang comprises 1, 2, or more nucleosides. In some embodiments, the 5′ overhang comprises 2 nucleosides. In some embodiments, the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 2856-3037, or a nucleic acid sequence thereof having 1 or 2 nucleoside additions at the 3′ end. In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a nucleoside sequence comprising or consisting of the sequence of any one of SEQ ID NOs: 2856-3037.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset A, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset A, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset A. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) MTRES1 mRNA. The siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset B, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset B, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset B. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) MTRES1 mRNA. The siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset C, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset C, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset C. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) MTRES1 mRNA. The siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset D, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset D, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset D. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) MTRES1 mRNA. The siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset E, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset E, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset E. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) MTRES1 mRNA. The siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset F, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset F, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA of subset F. In some embodiments, the siRNA is cross-reactive with a non-human primate (NHP) MTRES1 mRNA. The siRNA may include one or more internucleoside linkages and/or one or more nucleoside modifications.

In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with SEQ ID NO: 2576. In some embodiments, the sense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 2576, at least 80% identical to SEQ ID NO: 2576, at least 85% identical to SEQ ID NO: 2576, at least 90% identical to SEQ ID NO: 2576, or at least 95% identical to SEQ ID NO: 2576. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 2576, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 2576, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 2576. The sense strand may comprise any modifications or modification pattern described herein. The sense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety. In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with SEQ ID NO: 2638. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 2638, at least 80% identical to SEQ ID NO: 2638, at least 85% identical to SEQ ID NO: 2638, at least 90% identical to SEQ ID NO: 2638, or at least 95% identical to SEQ ID NO: 2638. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 2638, or an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 2638, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 2638. The antisense strand may comprise any modifications or modification pattern described herein. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety.

In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with SEQ ID NO: 2582. In some embodiments, the sense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 2582, at least 80% identical to SEQ ID NO: 2582, at least 85% identical to SEQ ID NO: 2582, at least 90% identical to SEQ ID NO: 2582, or at least 95% identical to SEQ ID NO: 2582. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 2582, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 2582, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 2582. The sense strand may comprise any modifications or modification pattern described herein. The sense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety. In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with SEQ ID NO: 2644. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 2644, at least 80% identical to SEQ ID NO: 2644, at least 85% identical to SEQ ID NO: 2644, at least 90% identical to SEQ ID NO: 2644, or at least 95% identical to SEQ ID NO: 2644. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 2644, or an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 2644, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 2644. The antisense strand may comprise any modifications or modification pattern described herein. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety.

In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with SEQ ID NO: 2583. In some embodiments, the sense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 2583, at least 80% identical to SEQ ID NO: 2583, at least 85% identical to SEQ ID NO: 2583, at least 90% identical to SEQ ID NO: 2583, or at least 95% identical to SEQ ID NO: 2583. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 2583, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 2583, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 2583. The sense strand may comprise any modifications or modification pattern described herein. The sense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety. In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with SEQ ID NO: 2645. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 2645, at least 80% identical to SEQ ID NO: 2645, at least 85% identical to SEQ ID NO: 2645, at least 90% identical to SEQ ID NO: 2645, or at least 95% identical to SEQ ID NO: 2645. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 2645, or an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 2645, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 2645. The antisense strand may comprise any modifications or modification pattern described herein. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety.

In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with SEQ ID NO: 2584. In some embodiments, the sense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 2584, at least 80% identical to SEQ ID NO: 2584, at least 85% identical to SEQ ID NO: 2584, at least 90% identical to SEQ ID NO: 2584, or at least 95% identical to SEQ ID NO: 2584. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 2584, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 2584, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 2584. The sense strand may comprise any modifications or modification pattern described herein. The sense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety. In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with SEQ ID NO: 2646. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 2646, at least 80% identical to SEQ ID NO: 2646, at least 85% identical to SEQ ID NO: 2646, at least 90% identical to SEQ ID NO: 2646, or at least 95% identical to SEQ ID NO: 2646. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 2646, or an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 2646, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 2646. The antisense strand may comprise any modifications or modification pattern described herein. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety.

In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with SEQ ID NO: 2604. In some embodiments, the sense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 2604, at least 80% identical to SEQ ID NO: 2604, at least 85% identical to SEQ ID NO: 2604, at least 90% identical to SEQ ID NO: 2604, or at least 95% identical to SEQ ID NO: 2604. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 2604, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 2604, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 2604. The sense strand may comprise any modifications or modification pattern described herein. The sense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety. In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with SEQ ID NO: 2666. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 2666, at least 80% identical to SEQ ID NO: 2666, at least 85% identical to SEQ ID NO: 2666, at least 90% identical to SEQ ID NO: 2666, or at least 95% identical to SEQ ID NO: 2666. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 2666, or an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 2666, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 2666. The antisense strand may comprise any modifications or modification pattern described herein. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety.

In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with SEQ ID NO: 2551. In some embodiments, the sense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 2551, at least 80% identical to SEQ ID NO: 2551, at least 85% identical to SEQ ID NO: 2551, at least 90% identical to SEQ ID NO: 2551, or at least 95% identical to SEQ ID NO: 2551. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 2551, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 2551, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 2551. The sense strand may comprise any modifications or modification pattern described herein. The sense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety. In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with SEQ ID NO: 2613. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 2613, at least 80% identical to SEQ ID NO: 2613, at least 85% identical to SEQ ID NO: 2613, at least 90% identical to SEQ ID NO: 2613, or at least 95% identical to SEQ ID NO: 2613. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 2613, or an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 2613, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 2613. The antisense strand may comprise any modifications or modification pattern described herein. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety.

In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with SEQ ID NO: 2681. In some embodiments, the sense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 2681, at least 80% identical to SEQ ID NO: 2681, at least 85% identical to SEQ ID NO: 2681, at least 90% identical to SEQ ID NO: 2681, or at least 95% identical to SEQ ID NO: 2681. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 2681, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 2681, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 2681. The sense strand may comprise any modifications or modification pattern described herein. The sense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety. In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with SEQ ID NO: 2863. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 2863, at least 80% identical to SEQ ID NO: 2863, at least 85% identical to SEQ ID NO: 2863, at least 90% identical to SEQ ID NO: 2863, or at least 95% identical to SEQ ID NO: 2863. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 2863, or an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 2863, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 2863. The antisense strand may comprise any modifications or modification pattern described herein. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety.

In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with SEQ ID NO: 2683. In some embodiments, the sense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 2683, at least 80% identical to SEQ ID NO: 2683, at least 85% identical to SEQ ID NO: 2683, at least 90% identical to SEQ ID NO: 2683, or at least 95% identical to SEQ ID NO: 2683. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 2683, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 2683, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 2683. The sense strand may comprise any modifications or modification pattern described herein. The sense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety. In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with SEQ ID NO: 2865. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 2865, at least 80% identical to SEQ ID NO: 2865, at least 85% identical to SEQ ID NO: 2865, at least 90% identical to SEQ ID NO: 2865, or at least 95% identical to SEQ ID NO: 2865. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 2865, or an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 2865, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 2865. The antisense strand may comprise any modifications or modification pattern described herein. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety.

In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with SEQ ID NO: 3284. In some embodiments, the sense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 3284, at least 80% identical to SEQ ID NO: 3284, at least 85% identical to SEQ ID NO: 3284, at least 90% identical to SEQ ID NO: 3284, or at least 95% identical to SEQ ID NO: 3284. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 3284, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 3284, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 3284. The sense strand may comprise any modifications or modification pattern described herein. The sense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety. In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with SEQ ID NO: 3295. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 3295, at least 80% identical to SEQ ID NO: 3295, at least 85% identical to SEQ ID NO: 3295, at least 90% identical to SEQ ID NO: 3295, or at least 95% identical to SEQ ID NO: 3295. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 3295, or an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 3295, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 3295. The antisense strand may comprise any modifications or modification pattern described herein. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety.

In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises an antisense oligonucleotide (ASO). In some embodiments, the ASO is 12-30 nucleosides in length. In some embodiments, the ASO is 14-30 nucleosides in length. In some embodiments, the ASO is at least about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleosides in length, or a range defined by any of the two aforementioned numbers. In some embodiments, the ASO is 15-25 nucleosides in length. In some embodiments, the ASO is 20 nucleosides in length.

In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises an ASO about 12-30 nucleosides in length and comprising a nucleoside sequence complementary to about 12-30 contiguous nucleosides of a full-length human MTRES1 mRNA sequence such as SEQ ID NO: 2443; wherein (i) the oligonucleotide comprises a modification comprising a modified nucleoside and/or a modified internucleoside linkage, and/or (ii) the composition comprises a pharmaceutically acceptable carrier. In some embodiments, the ASO comprise a nucleoside sequence complementary to at least about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more contiguous nucleosides of one of SEQ ID NO: 2443.

In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises an ASO about 12-30 nucleosides in length and comprising a nucleoside sequence complementary to about 12-30 contiguous nucleosides of a full-length human MTRES1 mRNA sequence such as SEQ ID NO: 2462; wherein (i) the oligonucleotide comprises a modification comprising a modified nucleoside and/or a modified internucleoside linkage, and/or (ii) the composition comprises a pharmaceutically acceptable carrier. In some embodiments, the ASO comprise a nucleoside sequence complementary to at least about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more contiguous nucleosides of one of SEQ ID NO: 2462.

In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises a modification comprising a modified nucleoside and/or a modified internucleoside linkage, and/or (ii) the composition comprises a pharmaceutically acceptable carrier. In some embodiments, the oligonucleotide comprises a modification comprising a modified nucleoside and/or a modified internucleoside linkage. In some embodiments, the oligonucleotide comprises a modified internucleoside linkage. In some embodiments, the modified internucleoside linkage comprises alkylphosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof. In some embodiments, the modified internucleoside linkage comprises one or more phosphorothioate linkages. A phosphorothioate may include a nonbridging oxygen atom in a phosphate backbone of the oligonucleotide that is replaced by sulfur. Modified internucleoside linkages may be included in siRNAs or ASOs. Benefits of the modified internucleoside linkage may include decreased toxicity or improved pharmacokinetics.

In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises a modified internucleoside linkage, wherein the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified internucleoside linkages, or a range of modified internucleoside linkages defined by any two of the aforementioned numbers. In some embodiments, the oligonucleotide comprises no more than 18 modified internucleoside linkages. In some embodiments, the oligonucleotide comprises no more than 20 modified internucleoside linkages. In some embodiments, the oligonucleotide comprises 2 or more modified internucleoside linkages, 3 or more modified internucleoside linkages, 4 or more modified internucleoside linkages, 5 or more modified internucleoside linkages, 6 or more modified internucleoside linkages, 7 or more modified internucleoside linkages, 8 or more modified internucleoside linkages, 9 or more modified internucleoside linkages, 10 or more modified internucleoside linkages, 11 or more modified internucleoside linkages, 12 or more modified internucleoside linkages, 13 or more modified internucleoside linkages, 14 or more modified internucleoside linkages, 15 or more modified internucleoside linkages, 16 or more modified internucleoside linkages, 17 or more modified internucleoside linkages, 18 or more modified internucleoside linkages, 19 or more modified internucleoside linkages, or 20 or more modified internucleoside linkages.

In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises the modified nucleoside. In some embodiments, the modified nucleoside comprises a locked nucleic acid (LNA), hexitol nucleic acid (HNA), cyclohexene nucleic acid (CeNA), 2′-O-methoxyethyl, 2′-O-alkyl, 2′-O-allyl, 2′-fluoro, or 2′-deoxy, or a combination thereof. In some embodiments, the modified nucleoside comprises an LNA. In some embodiments, the modified nucleoside comprises a 2′,4′ constrained ethyl nucleic acid. In some embodiments, the modified nucleoside comprises HLA. In some embodiments, the modified nucleoside comprises CeNA. In some embodiments, the modified nucleoside comprises a 2′-O-methoxyethyl group (“MOE”). In some embodiments, the modified nucleoside comprises a 2′-O-alkyl group. In some embodiments, the modified nucleoside comprises a 2′-O-allyl group. In some embodiments, the modified nucleoside comprises a 2′-fluoro group. In some embodiments, the modified nucleoside comprises a 2′-deoxy group. In some embodiments, the modified nucleoside comprises a 2′-O-methyl nucleoside, 2′-deoxyfluoro nucleoside, 2′-O—N-methylacetamido (2′-O-NMA) nucleoside, a 2′-O-dimethylaminoethoxyethyl(2′-O-DMAEOE) nucleoside, 2′-O-aminopropyl(2′-O-AP) nucleoside, or 2′-ara-F, or a combination thereof. In some embodiments, the modified nucleoside comprises a 2′-O-methyl nucleoside. In some embodiments, the modified nucleoside comprises a 2′-deoxyfluoro nucleoside. In some embodiments, the modified nucleoside comprises a 2′-O-NMA nucleoside. In some embodiments, the modified nucleoside comprises a 2′-O-DMAEOE nucleoside. In some embodiments, the modified nucleoside comprises a 2′-O-aminopropyl(2′-O-AP) nucleoside. In some embodiments, the modified nucleoside comprises 2′-ara-F. In some embodiments, the modified nucleoside comprises one or more 2′fluoro modified nucleosides. In some embodiments, the modified nucleoside comprises a 2′-O-alkyl modified nucleoside. In some embodiments, the modified nucleoside comprises a 2′-O-methyl inosine nucleoside. In some embodiments, the modified nucleoside comprises an unlocked nucleic acid. Benefits of the modified nucleoside may include decreased toxicity or improved pharmacokinetics.

In some embodiments, the modified nucleoside comprises an unlocked nucleic acid. An unlocked nucleic acid may comprise the following structure:

wherein the base can be any pyrimidine or purine.

In some embodiments, the oligonucleotide comprises a modified nucleoside. In some embodiments, the modified nucleoside comprises a locked nucleic acid and an abasic site:

where J and K are independently an H or a 3′ or 5′ linkage to a nucleotide via a phosphodiester or phosphorothioate bond.

In some embodiments, the oligonucleotide comprises a phosphate mimic. In some embodiments, the phosphate mimic comprises methylphosphonate. An example of a nucleotide that comprises a methylphosphonate is shown below:

(5′ methylphosphonate 2′-O-Methyl Uridine).

In some embodiments, the oligonucleotide comprises a duplex consisting of 21-36 nucleotide single strands with base pairing between 17-25 of the base pairs. In some embodiments, the duplex comprises blunt-ends at the 5′ or 3′ ends of each strand. One strand (antisense strand) is complementary to a target mRNA. Each end of the antisense strand has one to five phosphorothioate bonds. The 5′ end has an optional phosphate mimic such as a vinyl phosphonate. In some embodiments, the oligonucleotide is used to knock down a target mRNA or a target protein. In some embodiments, the sense strand has the same sequence as the target mRNA. In some embodiments, there are 1-5 phosphorothioates at the 5′ and 3′ ends.

In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 modified nucleosides, or a range of nucleosides defined by any two of the aforementioned numbers. In some embodiments, the oligonucleotide comprises no more than 19 modified nucleosides. In some embodiments, the oligonucleotide comprises no more than 21 modified nucleosides. In some embodiments, the oligonucleotide comprises 2 or more modified nucleosides, 3 or more modified nucleosides, 4 or more modified nucleosides, 5 or more modified nucleosides, 6 or more modified nucleosides, 7 or more modified nucleosides, 8 or more modified nucleosides, 9 or more modified nucleosides, 10 or more modified nucleosides, 11 or more modified nucleosides, 12 or more modified nucleosides, 13 or more modified nucleosides, 14 or more modified nucleosides, 15 or more modified nucleosides, 16 or more modified nucleosides, 17 or more modified nucleosides, 18 or more modified nucleosides, 19 or more modified nucleosides, 20 or more modified nucleosides, or 21 or more modified nucleosides.

In some embodiments, the sense strand comprises at least three modified nucleosides, wherein the three modifications comprise a 2′-fluoro modified nucleoside, a 2′-O-methyl modified nucleoside, and 2′-O-methoxyethyl. In some embodiments, the sense strand comprises at least two modified nucleosides, wherein the two modifications comprise a 2′-fluoro modified nucleoside, a 2′-O-methyl modified nucleoside, and 2′-O-methoxyethyl. In some embodiments, each nucleoside of the sense strand comprises a modified nucleoside, wherein the modified nucleosides are selected from the group consisting of a 2′-fluoro modified nucleoside, a 2′-O-methyl modified nucleoside, and 2′-O-methoxyethyl. In some embodiments, the sense strand comprises at least a 2′-fluoro modified nucleoside, a 2′-O-methyl modified nucleoside, and 2′-O-methoxyethyl.

In some embodiments, the antisense strand is combination of 2′-fluoro and 2′-O-Methyl modifications. In some embodiments, each nucleoside of the antisense strand comprises a modified nucleoside, wherein the modified nucleosides are selected from the group consisting of a 2′-fluoro modified nucleoside and a 2′-O-methyl modified nucleoside. In some embodiments, the sense strand comprises at least a 2′-fluoro modified nucleoside and a 2′-O-methyl modified nucleoside.

The oligonucleotide may include purines. Examples of purines include adenine (A), inosine (I), or guanine (G), or modified versions thereof. The oligonucleotide may include pyrimidines. Examples of pyrimidines include cytosine (C), thymine (T), or uracil (U), or modified versions thereof.

In some embodiments, the sense strand comprises purines and pyrimidines. In some embodiments, all purine nucleosides comprise 2′-fluoro, and all pyrimidine nucleosides are modified with a mixture of 2′-O-methyl and 2′-O-methoxyethyl. In some embodiments, all purine nucleosides comprise 2′-O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2′-fluoro and 2′-O-methoxyethyl. In some embodiments, all purine nucleosides comprise 2′-O-methoxyethyl, and all pyrimidine nucleosides are modified with a mixture of 2′-fluoro and 2′-O-methyl. In some embodiments, all pyrimidine nucleosides comprise 2′-fluoro, and all purine nucleosides are modified with a mixture of 2′-O-methyl and 2′-O-methoxyethyl. In some embodiments, all pyrimidine nucleosides comprise 2′-O-methyl, and all purine nucleosides are modified with a mixture of 2′-fluoro and 2′-O-methoxyethyl. In some embodiments, all pyrimidine nucleosides comprise 2′-O-methoxyethyl, and all purine nucleosides are modified with a mixture of 2′-fluoro and 2′-O-methyl. In some embodiments, the sense strand may include a 2′-deoxy nucleoside.

In some embodiments, at least one nucleotide at position 4 or 5 of the sense strand comprises a 2′-O-methoxyethyl modified nucleoside. In some embodiments, at least one nucleotide of the sense strand from position 6 to 9 comprise a 2′-fluoro-modified nucleoside. In some embodiments, at least two nucleotides of the sense strand at position 6 to 9 comprise a 2′-fluoro-modified nucleoside. In some embodiments, at least three nucleotides of the sense strand at positions 6 to 9 comprise a 2′-fluoro-modified nucleoside. In some embodiments, each nucleotide from positions 6 to 9 of the sense strand comprise a 2′-fluoro-modified nucleoside. In some embodiments, at least one nucleotide at position 16 to 20 of the sense strand comprises a 2′-O-methyl modified nucleoside. In some embodiments, at least two nucleotides at position 16 to 20 of the sense strand comprise a 2′-O-methyl modified nucleoside. In some embodiments, at least three nucleotides at position 16 to 20 of the sense strand comprise a 2′-O-methyl modified nucleoside. In some embodiments, at least four nucleotides at position 16 to 20 of the sense strand comprise a 2′-O-methyl modified nucleoside. In some embodiments, all nucleotides at position 16 to 20 of the sense strand comprise a 2′-O-methyl modified nucleoside.

In some embodiments, any of the following is true with regards to the antisense strand: all purine nucleosides comprise 2′-fluoro, and all pyrimidine nucleosides are modified with a mixture of 2′-fluoro and 2′-O-methyl; all purine nucleosides comprise 2′-O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2′-fluoro and 2′-O-methyl; all purine nucleosides comprise 2′-O-methyl, and all pyrimidine nucleosides comprise 2′-fluoro; all pyrimidine nucleosides comprise 2′-fluoro, and all purine nucleosides are modified with a mixture of 2′-fluoro and 2′-O-methyl; all pyrimidine nucleosides comprise 2′-O-methyl, and all purine nucleosides are modified with a mixture of 2′-fluoro and 2′-O-methyl; or all pyrimidine nucleosides comprise 2′-O-methyl, and all purine nucleosides comprise 2′-fluoro. In some embodiments, all purine nucleosides comprise 2′-fluoro, and all pyrimidine nucleosides are modified with a mixture of 2′-fluoro and 2′-O-methyl. In some embodiments, all purine nucleosides comprise 2′-O-methyl, and all pyrimidine nucleosides are modified with a mixture of 2′-fluoro and 2′-O-methyl; all purine nucleosides comprise 2′-O-methyl, and all pyrimidine nucleosides comprise 2′-fluoro. In some embodiments, all pyrimidine nucleosides comprise 2′-fluoro, and all purine nucleosides are modified with a mixture of 2′-fluoro and 2′-O-methyl; all pyrimidine nucleosides comprise 2′-O-methyl, and all purine nucleosides are modified with a mixture of 2′-fluoro and 2′-O-methyl. In some embodiments, all pyrimidine nucleosides comprise 2′-O-methyl, and all purine nucleosides comprise 2′-fluoro.

Some embodiments include an oligonucleotide comprising: a sense strand having a 5′ end, a 3′ end and a region of complementarity with an antisense strand; an antisense strand having a 5′end, a 3′end and a region of complementarity with the sense strand and a region of complementarity to an mRNA target; an overhang region at the 3′ end of the sense strand having at least 3 contiguous phosphorothioated nucleotides; and an overhang region at the 3′ end of the antisense strand having at least 3 contiguous phosphorothioated nucleotides.

Some embodiments include an oligonucleotide comprising: a sense strand having a 5′ end, a 3′ end and a region of complementarity with an antisense strand; an antisense strand having a 5′end, a 3′end and a region of complementarity with the sense strand and a region of complementarity to an mRNA target; and an overhang region at the 3′ end of the sense strand having at least 3 contiguous phosphorothioated nucleotides.

In some embodiments, the oligonucleotide includes two to eight oligonucleotides attached through a linker. The linker may be hydrophobic. In some embodiments, the oligonucleotides independently have substantial chemical stabilization (e.g., at least 40% of the constituent bases are chemically-modified). In some embodiments, the oligonucleotides have full chemical stabilization (i.e., all of the constituent bases are chemically-modified). In some embodiments, the oligonucleotide includes one or more single-stranded phosphorothioated tails, each independently having two to twenty nucleotides. In some embodiments, each single-stranded tail has eight to ten nucleotides.

In certain embodiments, a compound (e.g. moiety attached to the oligonucleotide) includes three properties: (1) a branched structure, (2) full metabolic stabilization, and (3) the presence of a single-stranded tail comprising phosphorothioate linkers. In a particular embodiment, a compound has 2 or 3 branches. The increased overall size of the branched structures promote increased uptake. Also, without being bound by a particular theory of activity, multiple adjacent branches (e.g., 2 or 3) allow each branch to act cooperatively and thus dramatically enhance rates of internalization, trafficking and release. The compound may include an oligonucleotide described herein, as part of the compound.

In certain embodiments, a compound includes the following properties: (1) two or more branched oligonucleotides linked via a non-natural linker (2) substantially chemically stabilized, e.g., wherein more than 40%, optimally 100%, of oligonucleotides are chemically modified (e.g., no RNA and optionally no DNA); and (3) phosphorothioated single oligonucleotides containing at least 3, optimally 5-20 phosphorothioated bonds.

In some embodiments, the oligonucleotide comprises a phosphate at a 5′ end. In some embodiments, the oligonucleotide comprises a phosphate at a 3′ end. In some embodiments, the oligonucleotide comprises a phosphate mimic at a 5′ end. In some embodiments, the oligonucleotide comprises a phosphate mimic at a 3′ end.

The oligonucleotide may include purines. Examples of purines include adenine (A), inosine (I), or guanine (G), or modified versions thereof. The oligonucleotide may include pyrimidines. Examples of pyrimidines include cytosine (C), thymine (T), or uracil (U), or modified versions thereof.

In some embodiments, purines of the oligonucleotide comprise 2′-fluoro modified purines. In some embodiments, purines of the oligonucleotide comprise 2′-O-methyl modified purines. In some embodiments, purines of the oligonucleotide comprise a mixture of 2′-fluoro and 2′-O-methyl modified purines. In some embodiments, all purines of the oligonucleotide comprise 2′-fluoro modified purines. In some embodiments, all purines of the oligonucleotide comprise 2′-O-methyl modified purines. In some embodiments, all purines of the oligonucleotide comprise a mixture of 2′-fluoro and 2′-O-methyl modified purines. 2′-O-methyl may include 2′-O-methyl. Where 2′-O-methyl modifications are described, it is contemplated that a 2′-methyl modification may be included, and vice versa.

In some embodiments, pyrimidines of the oligonucleotide comprise 2′-fluoro modified pyrimidines. In some embodiments, pyrimidines of the oligonucleotide comprise 2′-O-methyl modified pyrimidines. In some embodiments, pyrimidines of the oligonucleotide comprise a mixture of 2′-fluoro and 2′-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2′-fluoro modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2′-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise a mixture of 2′-fluoro and 2′-O-methyl modified pyrimidines.

In some embodiments, purines of the oligonucleotide comprise 2′-fluoro modified purines, and pyrimidines of the oligonucleotide comprise a mixture of 2′-fluoro and 2′-O-methyl modified pyrimidines. In some embodiments, purines of the oligonucleotide comprise 2′-O-methyl modified purines, and pyrimidines of the oligonucleotide comprise a mixture of 2′-fluoro and 2′-O-methyl modified pyrimidines. In some embodiments, purines of the oligonucleotide comprise 2′-fluoro modified purines, and pyrimidines of the oligonucleotide comprise 2′-O-methyl modified pyrimidines. In some embodiments, purines of the oligonucleotide comprise 2′-O-methyl modified purines, and pyrimidines of the oligonucleotide comprise 2′-fluoro modified pyrimidines. In some embodiments, pyrimidines of the oligonucleotide comprise 2′-fluoro modified pyrimidines, and purines of the oligonucleotide comprise a mixture of 2′-fluoro and 2′-O-methyl modified purines. In some embodiments, pyrimidines of the oligonucleotide comprise 2′-O-methyl modified pyrimidines, and purines of the oligonucleotide comprise a mixture of 2′-fluoro and 2′-O-methyl modified purines. In some embodiments, pyrimidines of the oligonucleotide comprise 2′-fluoro modified pyrimidines, and purines of the oligonucleotide comprise 2′-O-methyl modified purines. In some embodiments, pyrimidines of the oligonucleotide comprise 2′-O-methyl modified pyrimidines, and purines of the oligonucleotide comprise 2′-fluoro modified purines.

In some embodiments, all purines of the oligonucleotide comprise 2′-fluoro modified purines, and all pyrimidines of the oligonucleotide comprise a mixture of 2′-fluoro and 2′-O-methyl modified pyrimidines. In some embodiments, all purines of the oligonucleotide comprise 2′-O-methyl modified purines, and all pyrimidines of the oligonucleotide comprise a mixture of 2′-fluoro and 2′-O-methyl modified pyrimidines. In some embodiments, all purines of the oligonucleotide comprise 2′-fluoro modified purines, and all pyrimidines of the oligonucleotide comprise 2′-O-methyl modified pyrimidines. In some embodiments, all purines of the oligonucleotide comprise 2′-O-methyl modified purines, and all pyrimidines of the oligonucleotide comprise 2′-fluoro modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2′-fluoro modified pyrimidines, and all purines of the oligonucleotide comprise a mixture of 2′-fluoro and 2′-O-methyl modified purines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2′-O-methyl modified pyrimidines, and all purines of the oligonucleotide comprise a mixture of 2′-fluoro and 2′-O-methyl modified purines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2′-fluoro modified pyrimidines, and all purines of the oligonucleotide comprise 2′-O-methyl modified purines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2′-O-methyl modified pyrimidines, and all purines of the oligonucleotide comprise 2′-fluoro modified purines.

In some cases, the oligonucleotide comprises a particular modification pattern. In some embodiments, position 9 counting from the 5′ end of the of a strand of the oligonucleotide may have a 2′F modification. In some embodiments, when position 9 of a strand of the oligonucleotide is a pyrimidine, then all purines in a strand of the oligonucleotide have a 2′OMe modification. In some embodiments, when position 9 is the only pyrimidine between positions 5 and 11 of the sense stand, then position 9 is the only position with a 2′F modification in a strand of the oligonucleotide. In some embodiments, when position 9 and only one other base between positions 5 and 11 of a strand of the oligonucleotide are pyrimidines, then both of these pyrimidines are the only two positions with a 2′F modification in a strand of the oligonucleotide. In some embodiments, when position 9 and only two other bases between positions 5 and 11 of a strand of the oligonucleotide are pyrimidines, and those two other pyrimidines are in adjacent positions so that there would be not three 2′F modifications in a row, then any combination of 2′F modifications can be made that give three 2′F modifications in total. In some embodiments, when there are more than 2 pyrimidines between positions 5 and 11 of a strand of the oligonucleotide, then all combinations of pyrimidines having the 2′F modification are allowed that have three to five 2′F modifications in total, provided that a strand of the oligonucleotide does not have three 2′F modifications in a row. In some cases, a strand of the oligonucleotide of any of the siRNAs comprises a modification pattern which conforms to any or all of these a strand of the oligonucleotide rules.

In some embodiments, when position 9 of a strand of the oligonucleotide is a purine, then all purines in a strand of the oligonucleotide have a 2′OMe modification. In some embodiments, when position 9 is the only purine between positions 5 and 11 of the sense stand, then position 9 is the only position with a 2′F modification in a strand of the oligonucleotide. In some embodiments, when position 9 and only one other base between positions 5 and 11 of a strand of the oligonucleotide are purines, then both of these purines are the only two positions with a 2′F modification in a strand of the oligonucleotide. In some embodiments, when position 9 and only two other bases between positions 5 and 11 of a strand of the oligonucleotide are purines, and those two other purines are in adjacent positions so that there would be not three 2′F modifications in a row, then any combination of 2′F modifications can be made that give three 2′F modifications in total. In some embodiments, when there are more than 2 purines between positions 5 and 11 of a strand of the oligonucleotide, then all combinations of purines having the 2′F modification are allowed that have three to five 2′F modifications in total, provided that a strand of the oligonucleotide does not have three 2′F modifications in a row. In some cases, a strand of the oligonucleotide of any of the siRNAs comprises a modification pattern which conforms to any or all of these a strand of the oligonucleotide rules.

In some cases, position 9 of a strand of the oligonucleotide can be a 2′deoxy. In these cases, 2′F and 2′OMe modifications may occur at the other positions of a strand of the oligonucleotide. In some cases, a strand of the oligonucleotide of any of the siRNAs comprises a modification pattern which conforms to these a strand of the oligonucleotide rules.

In some embodiments, position nine of the sense strand comprises a 2′-fluoro-modified pyrimidine. In some embodiments, all purines of the sense strand comprise 2′-O-methyl modified purines. In some embodiments, 1, 2, 3, 4, or 5 pyrimidines between positions 5 and 11 comprise a 2′fluoro-modified pyrimidine, provided there are not three 2′-fluoro-modified pyrimidines in a row. In some embodiments, the odd-numbered positions of the antisense strand comprise 2′-O-methyl modified nucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2′fluoro-modified nucleotides and unmodified deoxyribonucleotide. In some embodiments, the even-numbered positions of the antisense strand comprise 2′fluoro-modified nucleotides, 2′-O-methyl modified nucleotides and unmodified deoxyribonucleotide. In some embodiments, position nine of the sense strand comprises a 2′-fluoro-modified pyrimidine; all purines of the sense strand comprises 2′-O-methyl modified purines; 1, 2, 3, 4, or 5 pyrimidines between positions 5 and 11 comprise a 2′fluoro-modified pyrimidine, provided there are not three 2′-fluoro-modified pyrimidines in a row; the odd-numbered positions of the antisense strand comprise 2′-O-methyl modified nucleotides; and the even-numbered positions of the antisense strand comprise 2′fluoro-modified nucleotides and unmodified deoxyribonucleotides.

In some embodiments, position nine of the sense strand comprises a 2′-fluoro-modified purine. In some embodiments, all pyrimidines of the sense strand comprise 2′-O-methyl modified purines. In some embodiments, 1, 2, 3, 4, or 5 purines between positions 5 and 11 comprise a 2′fluoro-modified purine, provided there are not three 2′-fluoro-modified purine in a row. In some embodiments, the odd-numbered positions of the antisense strand comprise 2′-O-methyl modified nucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2′fluoro-modified nucleotides and unmodified deoxyribonucleotide. In some embodiments, the even-numbered positions of the antisense strand comprise 2′fluoro-modified nucleotides, 2′-O-methyl modified nucleotides and unmodified deoxyribonucleotide. In some embodiments, position nine of the sense strand comprises a 2′-fluoro-modified purine; all pyrimidine of the sense strand comprises 2′-O-methyl modified pyrimidines; 1, 2, 3, 4, or 5 purines between positions 5 and 11 comprise a 2′fluoro-modified purines, provided there are not three 2′-fluoro-modified purines in a row; the odd-numbered positions of the antisense strand comprise 2′-O-methyl modified nucleotides; and the even-numbered positions of the antisense strand comprise 2′fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, there are not three 2′-fluoro-modified purines in a row. In some embodiments, there are not three 2′-fluoro-modified pyrimidines in a row.

In some embodiments, position nine of the sense strand comprises an unmodified deoxyribonucleotide. In some embodiments, positions 5, 7, and 8 of the sense strand comprise 2′fluoro-modified nucleotides. In some embodiments, all pyrimidines in positions 10 to 21 of the sense strand comprise 2′-O-methyl modified pyrimidines and all purines in positions 10 to 21 of the comprise 2′-O-methyl modified purines or 2′fluoro-modified purines. In some embodiments, the odd-numbered positions of the antisense strand comprise 2′-O-methyl modified nucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2′fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2′fluoro-modified nucleotides, 2′-O-methyl modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, position nine of the sense strand comprises an unmodified deoxyribonucleotide; positions 5, 7, and 8 of the sense strand comprise 2′fluoro-modified nucleotides; all pyrimidines in positions 10 to 21 of the sense strand comprise 2′-O-methyl modified pyrimidines and all purines in positions 10 to 21 of the comprise 2′-O-methyl modified purines or 2′fluoro-modified purines; the odd-numbered positions of the antisense strand comprise 2′-O-methyl modified nucleotides; and the even-numbered positions of the antisense strand comprise 2′fluoro-modified nucleotides and unmodified deoxyribonucleotides.

In some embodiments, position nine of the sense strand comprises an unmodified deoxyribonucleotide. In some embodiments, positions 5, 7, and 8 of the sense strand comprise 2′fluoro-modified nucleotides. In some embodiments, all purines in positions 10 to 21 of the sense strand comprise 2′-O-methyl modified purines and all pyrimidines in positions 10 to 21 of the comprise 2′-O-methyl modified pyrimidines or 2′fluoro-modified pyrimidines. In some embodiments, the odd-numbered positions of the antisense strand comprise 2′-O-methyl modified nucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2′fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, the even-numbered positions of the antisense strand comprise 2′fluoro-modified nucleotides, 2′-O-methyl modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, position nine of the sense strand comprises an unmodified deoxyribonucleotide; positions 5, 7, and 8 of the sense strand comprise 2′fluoro-modified nucleotides; all purines in positions 10 to 21 of the sense strand comprise 2′-O-methyl modified purines and all pyrimidines in positions 10 to 21 of the comprise 2′-O-methyl modified pyrimidines or 2′fluoro-modified pyrimidines; the odd-numbered positions of the antisense strand comprise 2′-O-methyl modified nucleotides; and the even-numbered positions of the antisense strand comprise 2′fluoro-modified nucleotides and unmodified deoxyribonucleotide.

In some embodiments, the moiety includes a negatively charged group attached at a 5′ end of the oligonucleotide. This may be referred to as a 5′-end group. In some embodiments, the negatively charged group is attached at a 5′ end of an antisense strand of an siRNA disclosed herein. The 5′-end group may be or include a 5′-end phosphorothioate, 5′-end phosphorodithioate, 5′-end vinylphosphonate (5′-VP), 5′-end methylphosphonate, 5′-end cyclopropyl phosphonate, or a 5′-deoxy-5′-C-malonyl. The 5′-end group may comprise 5′-VP. In some embodiments, the 5′-VP comprises a trans-vinylphosphonate or cis-vinylphosphonate. The 5′-end group may include an extra 5′ phosphate. A combination of 5′-end groups may be used.

In some embodiments, the oligonucleotide includes a negatively charged group. The negatively charged group may aid in cell or tissue penetration. The negatively charged group may be attached at a 5′ or 3′ end (e.g. a 5′ end) of the oligonucleotide. This may be referred to as an end group. The end group may be or include a phosphorothioate, phosphorodithioate, vinylphosphonate, methylphosphonate, cyclopropyl phosphonate, or a deoxy-C-malonyl. The end group may include an extra 5′ phosphate such as an extra 5′ phosphate. A combination of end groups may be used.

In some embodiments, the oligonucleotide includes a phosphate mimic. In some embodiments, the phosphate mimic comprises vinyl phosphonate. In some embodiments, the vinyl phosphonate comprises a trans-vinylphosphonate. In some embodiments, the vinyl phosphonate comprises a cis-vinylphosphonate. An example of a nucleotide that includes a vinyl phosphonate is shown below.

In some embodiments, the vinyl phosphonate increases the stability of the oligonucleotide. In some embodiments, the vinyl phosphonate increases the accumulation of the oligonucleotide in tissues. In some embodiments, the vinyl phosphonate protects the oligonucleotide from an exonuclease or a phosphatase. In some embodiments, the vinyl phosphonate improves the binding affinity of the oligonucleotide with the siRNA processing machinery.

In some embodiments, the oligonucleotide includes 1 vinyl phosphonate. In some embodiments, the oligonucleotide includes 2 vinyl phosphonates. In some embodiments, the oligonucleotide includes 3 vinyl phosphonates. In some embodiments, the oligonucleotide includes 4 vinyl phosphonates. In some embodiments, the antisense strand of the oligonucleotide comprises a vinyl phosphonate at the 5′ end. In some embodiments, the antisense strand of the oligonucleotide comprises a vinyl phosphonate at the 3′ end. In some embodiments, the sense strand of the oligonucleotide comprises a vinyl phosphonate at the 5′ end. In some embodiments, the sense strand of the oligonucleotide comprises a vinyl phosphonate at the 3′ end.

In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises a moiety attached at a 3′ or 5′ terminus of the oligonucleotide. Examples of moieties include a hydrophobic moiety or a sugar moiety, or a combination thereof. In some embodiments, the oligonucleotide is an siRNA having a sense strand, and the moiety is attached to a 5′ end of the sense strand. In some embodiments, the oligonucleotide is an siRNA having a sense strand, and the moiety is attached to a 3′ end of the sense strand. In some embodiments, the oligonucleotide is an siRNA having an antisense strand, and the moiety is attached to a 5′ end of the antisense strand. In some embodiments, the oligonucleotide is an siRNA having an antisense strand, and the moiety is attached to a 3′ end of the antisense strand. In some embodiments, the oligonucleotide is an ASO, and the moiety is attached to a 5′ end of the ASO. In some embodiments, the oligonucleotide is an ASO, and the moiety is attached to a 3′ end of the ASO.

In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises a hydrophobic moiety. The hydrophobic moiety may be attached at a 3′ or 5′ terminus of the oligonucleotide. The hydrophobic moiety may include a lipid such as a fatty acid. The hydrophobic moiety may include a hydrocarbon. The hydrocarbon may be linear. The hydrocarbon may be non-linear. The hydrophobic moiety may include a lipid moiety or a cholesterol moiety, or a combination thereof.

In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises a lipid attached at a 3′ or 5′ terminus of the oligonucleotide. In some embodiments, the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl stearyl, or α-tocopherol, or a combination thereof.

In some embodiments, the oligonucleotide comprises a lipophilic moiety attached at a 3′ or 5′ terminus of the oligonucleotide. In some embodiments, the lipophilic moiety comprises cholesterol, retinoic acid, cholic acid, adamantane acetic acid, 1-pyrene butyric acid, dihydrotestosterone, 1,3-bis-O(hexadecyl)glycerol, geranyloxyhexyanol, hexadecylglycerol, borneol, menthol, 1,3-propanediol, a heptadecyl group, palmitic acid, myristic acid, O3-(oleoyl) lithocholic acid, O3-(oleoyl) cholenic acid, ibuprofen, naproxen, dimethoxytrityl, or phenoxazine, or a combination thereof. The lipophilic moiety may include a steroid such as cholesterol. The lipophilic moiety may include retinoic acid. The lipophilic moiety may include cholic acid. The lipophilic moiety may include adamantane acetic acid. The lipophilic moiety may include 1-pyrene butyric acid. The lipophilic moiety may include dihydrotestosterone. The lipophilic moiety may include 1,3-bis-O(hexadecyl)glycerol. The lipophilic moiety may include geranyloxyhexyanol. The lipophilic moiety may include hexadecylglycerol. The lipophilic moiety may include borneol. The lipophilic moiety may include menthol. The lipophilic moiety may include 1,3-propanediol. The lipophilic moiety may include a heptadecyl group. The lipophilic moiety may include palmitic acid. The lipophilic moiety may include myristic acid. The lipophilic moiety may include 03-(oleoyl) lithocholic acid. The lipophilic moiety may include O3-(oleoyl) cholenic acid. The lipophilic moiety may include ibuprofen. The lipophilic moiety may include naproxen. The lipophilic moiety may include dimethoxytrityl. The lipophilic moiety may include phenoxazine.

4 30 In some embodiments, the lipophilic moiety comprises a hydrocarbon chain. The hydrocarbon chain may comprise or consist of a C-Chydrocarbon chain. In some embodiments, the lipophilic moiety comprises a lipid.

In some embodiments, the oligonucleotide includes one or more lipophilic monomers, containing one or more lipophilic moieties, conjugated to one or more positions on at least one strand of the oligonucleotide, optionally via a linker or carrier. For instance, some embodiments provide an oligonucleotide comprising: an antisense strand which is complementary to a target gene; a sense strand which is complementary to said antisense strand; and one or more lipophilic monomers, containing one or more lipophilic moieties, conjugated to one or more positions on at least one strand, optionally via a linker or carrier. In some embodiments, the lipophilicity of the lipophilic moiety, measured by octanol-water partition coefficient, logP, exceeds 0.

In some embodiments, the lipophilic moiety is an aliphatic, cyclic such as alicyclic, or polycyclic such as polyalicyclic compound, such as a steroid (e.g., sterol), a linear or branched aliphatic hydrocarbon, or an aromatic. Exemplary lipophilic moieties may include lipid, cholesterol, retinoic acid, cholic acid, adamantane acetic acid, 1-pyrene butyric acid, dihydrotestosterone, 1,3-bis-O(hexadecyl)glycerol, geranyloxyhexyanol, hexadecylglycerol, borneol, menthol, 1,3-propanediol, heptadecyl group, palmitic acid, myristic acid, O3-(oleoyl) lithocholic acid, O3-(oleoyl) cholenic acid, ibuprofen, naproxen, dimethoxytrityl, or phenoxazine. Suitable lipophilic moieties may also include those containing a saturated or unsaturated C4-C30 hydrocarbon chain (e.g., C4-C30 alkyl or alkenyl), and an optional functional group selected from the group consisting of hydroxyl, amine, carboxylic acid, sulfonate, phosphate, thiol, azide, and alkyne. The functional group may be useful to attach the lipophilic moiety to the oligonucleotide. In some embodiments, the lipophilic moiety contains a saturated or unsaturated C6-C18 hydrocarbon chain (e.g., a linear C6-C18 alkyl or alkenyl). In some embodiments, the lipophilic moiety contains a saturated or unsaturated C16 hydrocarbon chain (e.g., a linear C16 alkyl or alkenyl). In some embodiments, the lipophilic moiety contains two or more carbon-carbon double bonds.

In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises a hydrophobic moiety. The hydrophobic moiety may be attached at a 3′ or 5′ terminus of the oligonucleotide. The hydrophobic moiety may include a lipid such as a fatty acid. The hydrophobic moiety may include a hydrocarbon. The hydrocarbon may be linear. The hydrocarbon may be non-linear. The hydrophobic moiety may include a lipid moiety or a cholesterol moiety, or a combination thereof.

In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises a lipid attached at a 3′ or 5′ terminus of the oligonucleotide. In some embodiments, the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl, stearyl, or α-tocopherol, or a combination thereof.

In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises a hydrophobic ligand or moiety. In some embodiments, the hydrophobic ligand or moiety comprises cholesterol. In some embodiments, the hydrophobic ligand or moiety comprises a cholesterol derivative. In some embodiments, the hydrophobic ligand or moiety is attached at a 3′ terminus of the oligonucleotide. In some embodiments, the hydrophobic ligand or moiety s attached at a 5′ terminus of the oligonucleotide. In some embodiments, the composition comprises a sense strand, and the hydrophobic ligand or moiety is attached to the sense strand (e.g. attached to a 5′ end of the sense strand, or attached to a 3′ end of the sense strand). In some embodiments, the composition comprises an antisense strand, and the hydrophobic ligand or moiety is attached to the antisense strand (e.g. attached to a 5′ end of the antisense strand, or attached to a 3′ end of the antisense strand). In some embodiments, the composition comprises a hydrophobic ligand or moiety attached at a 3′ or 5′ terminus of the oligonucleotide.

In some embodiments, a hydrophobic moiety is attached to the oligonucleotide (e.g. a sense strand and/or an antisense strand of a siRNA). In some embodiments, a hydrophobic moiety is attached at a 3′ terminus of the oligonucleotide. In some embodiments, a hydrophobic moiety is attached at a 5′ terminus of the oligonucleotide. In some embodiments, the hydrophobic moiety comprises cholesterol. In some embodiments, the hydrophobic moiety includes a cyclohexanyl.

In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises a lipid attached at a 3′ or 5′ terminus of the oligonucleotide. In some embodiments, a lipid is attached at a 3′ terminus of the oligonucleotide. In some embodiments, a lipid is attached at a 5′ terminus of the oligonucleotide. In some embodiments, the lipid comprises cholesterol, myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl, stearyl, or α-tocopherol, or a combination thereof. In some embodiments, the lipid comprises stearyl, lithocholyl, docosanyl, docosahexaenyl, or myristyl. In some embodiments, the lipid comprises cholesterol. In some embodiments, the lipid includes a sterol such as cholesterol. In some embodiments, the lipid comprises stearyl, t-butylphenol, n-butylphenol, octylphenol, dodecylphenol, phenyl n-dodecyl, octadecylbenzamide, hexadecylbenzamide, or octadecylcyclohexyl. In some embodiments, the lipid comprises phenyl para C12.

In some embodiments, the oligonucleotide comprises any aspect of the following structure:

In some embodiments, R is not octane. In some embodiments, R is not an octane. In some embodiments, R is an alkyl group containing 4-7 or 9-18 carbons. In some embodiments, the oligonucleotide comprises any aspect of the following structure:

In some embodiments, the oligonucleotide comprises any aspect of the following structure:

8 In some embodiments, the oligonucleotide comprises any aspect of the following structure: The aspect included in the oligonucleotide may include the entire structure, or may include the lipid moiety, of any of the structures shown. In some embodiments, n is 1-3. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 carbons. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, R is an alkyl group. In some embodiments, the alkyl group contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbons. In some embodiments, the alkyl group contains 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 carbons, or a range defined by any two of the aforementioned numbers of carbons. In some embodiments, the alkyl group contains 12 carbons. In some embodiments, the alkyl group contains 14 carbons. In some embodiments, the alkyl group contains 15 carbons. In some embodiments, the alkyl group contains 16 carbons. In some embodiments, the alkyl group contains 18 carbons. In some embodiments, the alkyl group contains 4-18 carbons. In some embodiments, the oligonucleotide does not comprise a phenyloctyl group. In some embodiments, the alkyl group contains 11 carbons. In some embodiments, the alkyl group contains 12 carbons. In some embodiments, the alkyl group contains 13 carbons. In some embodiments, the alkyl group contains 14 carbons. In some embodiments, the alkyl group contains 15 carbons. In some embodiments, the alkyl group contains 16 carbons. In some embodiments, the alkyl group contains 17 carbons. In some embodiments, the alkyl group contains 18 carbons. In some embodiments, R is not an octane (C). In some embodiments, R includes a branched carbon chain. In some embodiments, R includes an unbranched carbon chain. In some embodiments, the lipid moiety comprises an alcohol or ether. In some embodiments, the lipid moiety has at least one degree of unsaturation. In some embodiments, the lipid moiety is an omega fatty acid, such as an omega-3, omega-5, omega-6, omega-7, or omega-9 fatty acid.

In some embodiments, the lipid includes a fatty acid. In some embodiments, the lipid comprises a lipid depicted in Table 1. The example lipid moieties in Table 1 are shown attached at a 5′ end of an oligonucleotide, in which the 5′ terminal phosphate of the oligonucleotide is shown with the lipid moiety. In some embodiments, a lipid moiety in Table 1 may be attached at a different point of attachment than shown. For example, the point of attachment of any of the lipid moieties in the table may be at a 3′ oligonucleotide end. In some embodiments, the lipid is used for targeting the oligonucleotide to a non-hepatic cell or tissue.

TABLE 1 Hydrophobic moiety examples Hydrophobic Hydrophobic Moiety Description Moiety Name Example Conjugation stearly ETL3  t-butylphenyl ETL7  n-butylphenyl ETL8  octylphenyl ETL9  dodecylphenyl (mixture of ortho and para) ETL10 phenyl n-dodecyl ETL12 octadecylbenzamide ETL13 hexadecylbenzamide ETL15 octadecylcyclohexyl ETL16 Myristamido methylphenyl ETL18 Lauramido methylphenyl ETL19 Palmitoamidoethyl- phenyl ETL20

In some embodiments, the lipid or lipid moiety includes 16 to 18 carbons. In some embodiments, the lipid includes 16 carbons. In some embodiments, the lipid includes 17 carbons. In some embodiments, the lipid includes 18 carbons. In some embodiments, the lipid moiety includes 16 carbons. In some embodiments, the lipid moiety includes 17 carbons. In some embodiments, the lipid moiety includes 18 carbons. In some embodiments, the lipid moiety includes 19 carbons. In some embodiments, the lipid moiety includes 20 carbons.

The hydrophobic moiety may include a linker that comprises a carbocycle. The carbocycle may be six-membered. Some examples of a carbocycle include phenyl or cyclohexyl. The linker may include a phenyl. The linker may include a cyclohexyl. The lipid may be attached to the carbocycle, which may in turn be attached at a phosphate (e.g. 5′ or 3′ phosphate) of the oligonucleotide. In some embodiments, the lipid or hydrocarbon, and the end of the sense are connected to the phenyl or cyclohexyl linker in the 1,4; 1,3; or 1,2 substitution pattern (e.g. the para, meta, or ortho phenyl configuration). In some embodiments, the lipid or hydrocarbon, and the end of the sense are connected to the phenyl or cyclohexyl linker in the 1,4-substitution pattern (e.g. the para phenyl configuration). The lipid may be attached to the carbocycle in the 1,4-substitution pattern relative to the oligonucleotide. The lipid may be attached to the carbocycle in the 1,3-substitution pattern relative to the oligonucleotide. The lipid may be attached to the carbocycle in the 1,2-substitution pattern relative to the oligonucleotide. The lipid may be attached to the carbocycle in the ortho orientation relative to the oligonucleotide. The lipid may be attached to the carbocycle in the para orientation relative to the oligonucleotide. The lipid may be attached to the carbocycle in the meta orientation relative to the oligonucleotide.

The lipid moiety may comprise or consist of the following structure:

In some embodiments, the lipid moiety comprises or consists of the following structure:

In some embodiments, the lipid moiety comprises the following structure:

In some embodiments, the lipid moiety comprises or consist of the following structure:

In some embodiments, the dotted line indicates a covalent connection. The covalent connection may between an end of the sense or antisense strand. For example, the connection may be to the 5′ end of the sense strand. In some embodiments, n is 0-3. In some embodiments, n is 1-3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, R includes a branched carbon chain. In some embodiments, R includes an unbranched carbon chain. In some embodiments, R is an alkyl group. In some embodiments, the alkyl group contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbons. In some embodiments, the alkyl group contains 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 carbons, or a range defined by any two of the aforementioned numbers of carbons. In some embodiments, the alkyl group contains 11 carbons. In some embodiments, the alkyl group contains 12 carbons. In some embodiments, the alkyl group contains 13 carbons. In some embodiments, the alkyl group contains 14 carbons. In some embodiments, the alkyl group contains 15 carbons. In some embodiments, the alkyl group contains 16 carbons. In some embodiments, the alkyl group contains 17 carbons. In some embodiments, the alkyl group contains 18 carbons. In some embodiments, R comprises or consists of an alkyl group containing 4-18 carbons. In some embodiments, the lipid moiety is not a phenyloctyl group. In some embodiments, R is not octane. In some embodiments, R is a carbon chain containing 4-7 or 9-18 carbons. In some embodiments, the lipid moiety is not a phenyloctyl group.

In some embodiments, the 5′ hydrophobic moiety comprises any one of the following structures:

wherein the dotted line indicates a covalent connection to the end of the 5′ end of the sense strand, n is 1-3, and R is an alkyl group containing 4-18 carbons. In some embodiments, R is not an octane. In some embodiments, the alkyl group contains 4-7 or 9-18 carbons. In some embodiments, the alkyl group contains 14 carbons. In some embodiments, the alkyl group contains 15 carbons. In some embodiments, the alkyl group contains 16 carbons. In some embodiments, the alkyl group contains 17 carbons. In some embodiments, the alkyl group contains 18 carbons. In some embodiments, the 5′ hydrophobic moiety comprises a hydrophobic moiety in Table 1. In some embodiments, the 5′ hydrophobic moiety comprises phenyl para C12. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14. In some embodiments, n is 0-3. In some embodiments, n is 1-3. In some embodiments, n is 1. In some embodiments n is 2. In some embodiments, the hydrophobic moiety comprises an alcohol or an ether. In some embodiments, R is an unsaturated alkyl group. In some embodiments, the unsaturated alkyl group may be monounsaturated. In some embodiments, the unsaturated alkyl group may be unsaturated at the omega-3, position, omega-4 position, omega-5 position, omega-6 position, omega-7 position, omega-8 position, omega-9 position, or a combination thereof. In some embodiments, the 5′ hydrophobic moiety is not a phenyloctyl group.

The hydrophobic moiety may include a linker that comprises a carbocycle. The carbocycle may be six-membered. Some examples of a carbocycle include phenyl or cyclohexyl. The linker may include a phenyl. The linker may include a cyclohexyl. The lipid may be attached to the carbocycle, which may in turn be attached at a phosphate (e.g. 5′ or 3′ phosphate) of the oligonucleotide. In some embodiments, the lipid or hydrocarbon, and the end of the sense are connected to the phenyl or cyclohexyl linker in the 1,4; 1,3; or 1,2 substitution pattern (e.g. the para, meta, or ortho phenyl configuration). In some embodiments, the lipid or hydrocarbon, and the end of the sense are connected to the phenyl or cyclohexyl linker in the 1,4-substitution pattern (e.g. the para phenyl configuration). The lipid may be attached to the carbocycle in the ortho orientation relative to the oligonucleotide. The lipid may be attached to the carbocycle in the para orientation relative to the oligonucleotide. The lipid may be attached to the carbocycle in the meta orientation relative to the oligonucleotide. The lipid may be attached to the carbocycle in the in the 1,4 orientation relative to the oligonucleotide. The lipid may be attached to the carbocycle in the in the 1,3 orientation relative to the oligonucleotide. The lipid may be attached to the carbocycle in the in the 1,2 orientation relative to the oligonucleotide.

In some embodiments, when the lipid moiety comprises the structure:

R is not an octyl group. In some embodiments, R is an unsaturated hydrocarbon. In some embodiments, R is a monounsaturated acyl group. In some embodiments, the monounsaturated acyl group is unsaturated at the omega-3, omega-5, omega-6, omega-7, omega-8, or omega-9 position. In some embodiments, the unsaturated hydrocarbon is a polyunsaturated fatty acyl group. In some embodiments, the polyunsaturated fatty acyl group is unsaturated at least at the omega-3, omega-5, omega-6, omega-7, omega-, omega-9 position, or a combination thereof.

The lipid moiety may be attached at a 5′ end of the oligonucleotide. The 5′ end may have one phosphate linking the lipid moiety to a 5′ carbon of a sugar of the oligonucleotide. The 5′ end may have two phosphates linking the lipid moiety to a 5′ carbon of a sugar of the oligonucleotide. The 5′ end may have three phosphates linking the lipid moiety to a 5′ carbon of a sugar of the oligonucleotide. The 5′ end may have one phosphate connected to the 5′ carbon of a sugar of the oligonucleotide, where the one phosphate is connected to the lipid moiety. The 5′ end may have two phosphates connected to the 5′ carbon of a sugar of the oligonucleotide, where the one of the two phosphates is connected to the lipid moiety. The 5′ end may have three phosphates connected to the 5′ carbon of a sugar of the oligonucleotide, where the one of the three phosphates is connected to the lipid moiety. The sugar may include a ribose. The sugar may include a deoxyribose. The sugar may be modified a such as a 2′-modified sugar (e.g. a 2′-O-methyl or 2′-fluoro ribose). A phosphate of the 5′ end may include a modification such as a sulfur in place of an oxygen. Two phosphates of the 5′ end may include a modification such as a sulfur in place of an oxygen. Three phosphates of the 5′ end may include a modification such as a sulfur in place of an oxygen.

In some embodiments, the oligonucleotide includes 1 lipid moiety. In some embodiments, the oligonucleotide includes 2 lipid moieties. In some embodiments, the oligonucleotide includes 3 lipid moieties. In some embodiments, the oligonucleotide includes 4 lipid moieties.

Some embodiments relate to a method of making an oligonucleotide comprising a hydrophobic conjugate. A strategy for making hydrophobic conjugates may include use of a phosphoramidite reagent based upon a 6-membered ring alcohol such as a phenol or cyclohexanol. The phosphoramidite may be reacted to a nucleotide to connect the nucleotide to the hydrophobic moiety, and thereby produce the hydrophobic conjugate. Some examples of phosphoramidite reagents that may be used to produce a hydrophobic conjugate are provided as follows:

In some embodiments, n is 1-3. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, R is an alkyl group. In some embodiments, the alkyl group contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbons. In some embodiments, the alkyl group contains 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 carbons, or a range defined by any two of the aforementioned numbers of carbons. In some embodiments, R comprises or consists of an alkyl group containing 4-18 carbons. Any one of the phosphoramidite reagents may be reacted to a 5′ end of an oligonucleotide to produce an oligonucleotide comprising a hydrophobic moiety. In some embodiments, the phosphoramidite reagents is reacted to a 5′ end of a sense strand of an siRNA. The sense strand may then be hybridized to an antisense strand to form a duplex. The hybridization may be performed by incubating the sense and antisense strands in solution at a given temperature. The temperature may be gradually reduced. The temperature may comprise or include a temperature comprising an annealing temperature for the sense and antisense strands. The temperature may be below or include a temperature below the annealing temperature for the sense and antisense strands. The temperature may be below a melting temperature of the sense and antisense strands.

The lipid may be attached to the oligonucleotide by a linker. The linker may include a polyethyleneglycol (e.g. tetraethyleneglycol).

The modifications described herein may be useful for delivery to a cell or tissue, for example, extrahepatic delivery or targeting of an oligonucleotide composition. The modifications described herein may be useful for targeting an oligonucleotide composition to a cell or tissue.

In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises a sugar moiety. The sugar moiety may include an N-acetyl galactose moiety (e.g. an N-acetylgalactosamine (GalNAc) moiety), an N-acetyl glucose moiety (e.g. an N-acetylglucosamine (GlcNAc) moiety), a fucose moiety, or a mannose moiety. The sugar moiety may include 1, 2, 3, or more sugar molecules. The sugar moiety may be attached at a 3′ or 5′ terminus of the oligonucleotide. The sugar moiety may include an N-acetyl galactose moiety. The sugar moiety may include an N-acetylgalactosamine (GalNAc) moiety. The sugar moiety may include an N-acetyl glucose moiety. The sugar moiety may include N-acetylglucosamine (GlcNAc) moiety. The sugar moiety may include a fucose moiety. The sugar moiety may include a mannose moiety. N-acetyl glucose, GlcNAc, fucose, or mannose may be useful for targeting macrophages when they target or bind a mannose receptor such as CD206. The sugar moiety may be useful for binding or targeting an asialoglycoprotein receptor such as an asialoglycoprotein receptor of a hepatocyte. The GalNAc moiety may bind to an asialoglycoprotein receptor. The GalNAc moiety may target a hepatocyte.

In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises an N-acetylgalactosamine (GalNAc) moiety. GalNAc may be useful for hepatocyte targeting. The GalNAc moiety may include a bivalent or trivalent branched linker. The oligo may be attached to 1, 2 or 3 GalNAcs through a bivalent or trivalent branched linker. The GalNAc moiety may include 1, 2, 3, or more GalNAc molecules. The GalNAc moiety may be attached at a 3′ or 5′ terminus of the oligonucleotide.

In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises an N-acetylgalactosamine (GalNAc) ligand for hepatocyte targeting. In some embodiments, the composition comprises GalNAc. In some embodiments, the composition comprises a GalNAc derivative. In some embodiments, the GalNAc ligand is attached at a 3′ terminus of the oligonucleotide. In some embodiments, the GalNAc ligand is attached at a 5′ terminus of the oligonucleotide. In some embodiments, the composition comprises a sense strand, and the GalNAc ligand is attached to the sense strand (e.g. attached to a 5′ end of the sense strand, or attached to a 3′ end of the sense strand). In some embodiments, the composition comprises an antisense strand, and the GalNAc ligand is attached to the antisense strand (e.g. attached to a 5′ end of the antisense strand, or attached to a 3′ end of the antisense strand). In some embodiments, the composition comprises a GalNAc ligand attached at a 3′ or 5′ terminus of the oligonucleotide.

Disclosed herein, in some embodiments, are compositions comprising an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises a GalNAc moiety. The GalNAc moiety may be included in any formula, structure, or GalNAc moiety shown below. In some embodiments, described herein is a compound (e.g. oligonucleotide) represented by Formula (I) or (II):

or a salt thereof, wherein J is an oligonucleotide; each w is independently selected from any value from 1 to 20; each v is independently selected from any value from 1 to 20; n is selected from any value from 1 to 20; m is selected from any value from 1 to 20; z is selected from any value from 1 to 3, wherein if z is 3, Y is C if z is 2, Y is CR6, or 6 2 if z is 1, Y is C(R); Q is selected from: 3-10 2 2 2 2 2 1-6 1-6 2 2 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 Ccarbocycle optionally substituted with one or more substituents independently selected from halogen, —CN, —NO, —OR, —SR, —N(R), —C(O)R, —C(O)N(R), —N(R)C(O)R, —N(R)C(O)N(R), —OC(O)N(R), —N(R)C(O)OR, —C(O)OR, —OC(O)R, —S(O)R, and Calkyl, wherein the Calkyl, is optionally substituted with one or more substituents independently selected from halogen, —CN, —OH, —SH, —NO, and —NH; 1 Ris a linker selected from: 7 7 7 7 7 7 7 7 7 7 7 7 − − − − − 7 7 7 7 7 7 7 7 7 7 2 2 2 2 2 —O—, —S—, —N(R)—, —C(O)—, —C(O)N(R)—, —N(R)C(O)—, —N(R)C(O)N(R)—, —OC(O)N(R)—, —N(R)C(O)O—, —C(O)O—, —OC(O)—, —S(O)—, —S(O)—, —OS(O)—, —OP(O)(OR)O—, —SP(O)(OR)O—, —OP(S)(OR)O—, —OP(O)(SR)O—, —OP(O)(OR)S—, —OP(O)(O)O—, —SP(O)(O)O—, —OP(S)(O)O—, —OP(O)(S)O—, —OP(O)(O) S—, —OP(O)(OR)NR—, —OP(O)(N(R))NR—, —OP(OR)O—, —OP(N(R))O—, —OP(OR)N(R)—, and —OPN(R)NR—; 2 each Ris independently selected from: 1-6 2 2 2 2 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 Calkyl optionally substituted with one or more substituents independently selected from halogen, —OR, —SR, —N(R), —C(O)R, —C(O)N(R), —N(R)C(O)R, —N(R)C(O)N(R), —OC(O)N(R), —N(R)C(O)OR, —C(O)OR, —OC(O)R, and —S(O)R; 3 4 Rand Rare each independently selected from: 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 2 2 2 2 —OR, —SR, —N(R), —C(O)R, —C(O)N(R), —N(R)C(O)R, —N(R)C(O)N(R), —OC(O)N(R), —N(R)C(O)OR, —C(O)OR, —OC(O)R, and —S(O)R; 5 each Ris independently selected from: 7 7 7 7 1 7 1 7 7 7 7 2 2 2 —OC(O)R, —OC(O)N(R), —N(R)C(O)R, —N(R)C(O)N(R), —N(R)C(O)OR, —C(O)R, —C(O)OR, and —C(O)N(R); 6 each Ris independently selected from: hydrogen; 2 2 2 2 2 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 halogen, —CN, —NO, —OR, —SR, —N(R), —C(O)R, —C(O)N(R), —N(R)C(O)R, —N(R)C(O)N(R), —OC(O)N(R), —N(R)C(O)OR, —C(O)OR, —OC(O)R, and —S(O)R; and 1-6 2 2 2 2 2 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 Calkyl optionally substituted with one or more substituents independently selected from halogen, —CN, —NO, —OR, —SR, —N(R), —C(O)R, —C(O)N(R), —N(R)C(O)R, —N(R)C(O)N(R), —OC(O)N(R), —N(R)C(O)OR, —C(O)OR, —OC(O)R, and —S(O)R; 7 each Ris independently selected from: hydrogen; 1-6 2-6 2-6 2 2 1-6 1-6 1-6 1-6 3-10 Calkyl, Calkenyl, and Calkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, —CN, —OH, —SH, —NO, —NH, ═O, ═S, —O—Calkyl, —S—Calkyl, —N(Calkyl) 2, —NH(Calkyl), Ccarbocycle, and 3- to 10-membered heterocycle; and 3-10 2 2 1-6 1-6 1-6 1-6 1-6 2-6 2-6 3-10 1-6 Ccarbocycle, and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —CN, —OH, —SH, —NO, —NH, ═O, ═S, —O—Calkyl, —S—Calkyl, —N(Calkyl) 2, —NH(Calkyl), Calkyl, Calkenyl, Calkynyl, Ccarbocycle, 3- to 10-membered heterocycle, and Chaloalkyl.

5-6 2 2 2 2 2 5-6 2 2 2 2 2 2 2 1-3 2 1-3 2 1-3 2 2 2 2 2 2 1-6 2 2 1-6 1-6 1-6 1-6 3-10 1-6 2 2 1-6 1-6 1-6 1-6 1-6 2 2 1-3 1 3 3 3 3 7 7 7 7 7 7 7 1 7 7 7 7 7 7 7 1 7 7 7 7 1 7 7 7 7 7 7 7 7 7 7 1 7 7 7 7 7 − − − − 7 1 7 7 7 1 7 7 2 7 7 7 7 7 7 2 7 7 7 7 2 7 7 3 7 7 7 7 7 7 3 7 7 7 7 3 7 7 4 7 7 7 7 7 7 4 7 7 7 7 4 7 7 5 7 7 7 7 7 7 7 7 5 7 7 7 7 7 1 7 7 7 2 3 4 5 In some embodiments, each w is independently selected from any value from 1 to 10. In some embodiments, each w is independently selected from any value from 1 to 5. In some embodiments, each w is 1. In some embodiments, each v is independently selected from any value from 1 to 10. In some embodiments, each v is independently selected from any value from 1 to 5. In some embodiments, each v is 1. In some embodiments, n is selected from any value from 1 to 10. In some embodiments, n is selected from any value from 1 to 5. In some embodiments, n is 2. In some embodiments, m is selected from any value from 1 to 10. In some embodiments, m is selected from any value from 1 to 5. In some embodiments, m is selected from 1 and 2. In some embodiments, z is 3 and Y is C. In some embodiments, Q is selected from Ccarbocycle optionally substituted with one or more substituents independently selected from halogen, —CN, —NO, —OR, —SR, —N(R), —C(O)R, —C(O)N(R), —N(R)C(O)R, —N(R)C(O)N(R), —OC(O)N(R), —N(R)C(O)OR, —C(O)OR, —OC(O)R, and —S(O)R. In some embodiments, Q is selected from Ccarbocycle optionally substituted with one or more substituents independently selected from halogen, —CN, —OH, —SH, —NO, and —NH. In some embodiments, Q is selected from phenyl and cyclohexyl, each of which is optionally substituted with one or more substituents independently selected from halogen, —CN, —OH, —SH, —NO, and —NH. In some embodiments, Q is selected from phenyl. In some embodiments, Q is selected from cyclohexyl. In some embodiments, Ris selected from —OP(O)(OR)O—, —SP(O)(OR)O—, —OP(S)(OR)O—, —OP(O)(SR)O—, —OP(O)(OR)S—, —OP(O)(O—)O—, —SP(O)(O—)O—, —OP(S)(O)O—, —OP(O)(S—)O—, —OP(O)(O—)S—, —OP(O)(OR)NR—, —OP(O)(N(R))NR—, —OP(OR)O—, —OP(N(R))O—, —OP(OR)N(R)—, and —OPN(R). NR. In some embodiments, Ris selected from —OP(O)(OR)O—, —SP(O)(OR)O—, —OP(S)(OR)O—, —OP(O)(SR)O—, —OP(O)(OR)S—, —OP(O)(O)O—, —SP(O)(O)O—, —OP(S)(O)O—, —OP(O)(S)O—, —OP(O)(O)S—, and —OP(OR)O—. In some embodiments, Ris selected from —OP(O)(OR)O—, —OP(S)(OR)O—, —OP(O)(O)O—, —OP(S)(O)O—, —OP(O)(S)O—, and —OP(OR)O—. In some embodiments, Ris selected from —OP(O)(OR)O— and —OP(OR)O—. In some embodiments, Ris selected from Calkyl substituted with one or more substituents independently selected from halogen, —OR, —OC(O)R, —SR, —N(R), —C(O)R, and —S(O)R. In some embodiments, Ris selected from Calkyl substituted with one or more substituents independently selected from —OR, —OC(O)R, —SR, and —N(R). In some embodiments, Ris selected from Calkyl substituted with one or more substituents independently selected from —ORand —OC(O)R. In some embodiments, Ris selected from halogen, —OR, —SR, —N(R), —C(O)R, —OC(O)R, and —S(O)R. In some embodiments, Ris selected from —OR—SR, —OC(O)R, and —N(R). In some embodiments, Ris selected from —OR— and —OC(O)R. In some embodiments, Ris selected from halogen, —OR, —SR, —N(R), —C(O)R, —OC(O)R, and —S(O)R. In some embodiments, Ris selected from —OR—SR, —OC(O)R, and —N(R). In some embodiments, Ris selected from —OR— and —OC(O)R. In some embodiments, Ris selected from —OC(O)R, —OC(O)N(R), —N(R)C(O)R, —N(R)C(O)N(R), and —N(R)C(O)OR. In some embodiments, Ris selected from —OC(O)Rand —N(R)C(O)R. In some embodiments, each R′ is independently selected from: hydrogen; and Calkyl optionally substituted with one or more substituents independently selected from halogen, —CN, —OH, —SH, —NO, —NH, ═O, ═S, —O—Calkyl, —S—Calkyl, —N(Calkyl) 2, —NH(Calkyl), Ccarbocycle, or 3- to 10-membered heterocycle. In some embodiments, each Ris independently selected from Calkyl optionally substituted with one or more substituents independently selected from halogen, —CN, —OH, —SH, —NO, —NH, —O, ═S, —O—Calkyl, —S—Calkyl, —N(Calkyl) 2, and —NH(Calkyl). In some embodiments, each Ris independently selected from Calkyl optionally substituted with one or more substituents independently selected from halogen, —CN, —OH, and —SH. In some embodiments, w is 1; v is 1; n is 2; m is 1 or 2; z is 3 and Y is C; Q is phenyl or cyclohexyl, each of which is optionally substituted with one or more substituents independently selected from halogen, —CN, —OH, —SH, —NO, —NH, and Calkyl; Ris selected from —OP(O)(OR)O—, —OP(S)(OR)O—, —OP(O)(O—)O—, —OP(S)(O)O—, —OP(O)(S—)O—, and —OP(OR)O—; Ris Calkyl substituted with —OH or —OC(O)CH; Ris —OH or —OC(O)CH; Ris —OH or —OC(O)CH; and Ris —NH(O)CH. In some embodiments, the compound comprises:

In some embodiments, the oligonucleotide (J) is attached at a 5′ end or a 3′ end of the oligonucleotide. In some embodiments, the oligonucleotide comprises DNA. In some embodiments, the oligonucleotide comprises RNA. In some embodiments, the oligonucleotide comprises one or more modified internucleoside linkages. In some embodiments, the one or more modified internucleoside linkages comprise alkylphosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof. In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified internucleoside linkages. In some embodiments, the compound binds to an asialoglycoprotein receptor. In some embodiments, the compound targets a hepatocyte.

Some embodiments include the following, where J is the oligonucleotide:

one or more additional phosphates, or one or more phosphorothioates linking to the oligonucleotide. J may include one or more additional phosphates linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide.

Some embodiments include the following, where J is the oligonucleotide:

J may include one or more additional phosphates, or one or more phosphorothioates linking to the oligonucleotide. J may include one or more additional phosphates linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide.

Some embodiments include the following, where J is the oligonucleotide:

J may include one or more phosphates or phosphorothioates linking to the oligonucleotide. J may include one or more phosphates linking to the oligonucleotide. J may include a phosphate linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide. J may include a phosphorothioate linking to the oligonucleotide.

Some embodiments include the following, where J is the oligonucleotide:

The structure in this compound attached to the oligonucleotide (J) may be referred to as “ETL17,” and is an example of a GalNAc moiety. J may include one or more phosphates or phosphorothioates linking to the oligonucleotide. J may include one or more phosphates linking to the oligonucleotide. J may include a phosphate linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide. J may include a phosphorothioate linking to the oligonucleotide.

Some embodiments include the following, where the phosphate or “5″” indicates a connection to the oligonucleotide:

Some embodiments include the following, where the phosphate or “5” indicates a connection to the oligonucleotide:

Some embodiments include the following, where J is the oligonucleotide:

include one or more phosphates or phosphorothioates linking to the oligonucleotide. J may include one or more phosphates linking to the oligonucleotide. J may include a phosphate linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide. J may include a phosphorothioate linking to the oligonucleotide.

Some embodiments include the following, where J is the oligonucleotide:

The structure in this compound attached to the oligonucleotide (J) may be referred to as “ETL1,” and is an example of a GalNAc moiety. J may include one or more phosphates or phosphorothioates linking to the oligonucleotide. J may include one or more phosphates linking to the oligonucleotide. J may include a phosphate linking to the oligonucleotide. J may include one or more phosphorothioates linking to the oligonucleotide. J may include a phosphorothioate linking to the oligonucleotide.3. siRNA Modification Patterns

In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises modification pattern 1S: 5′-NfsnsNfnNfnNfNfNfnNfnNfnNfnNfnNfsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 2S: 5′-nsnsnnNfnNfNfNfnnnnnnnnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 3S: 5′-nsnsnnNfnNfnNfnnnnnnnnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 4S: 5′-NfsnsNfnNfnNfNfNfnNfnNfnNfnNfnNfsnsnN-moiety-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, and N comprises one or more nucleosides. In some embodiments, the sense strand comprises modification pattern 5S: 5′-nsnsnnNfnNfNfNfnnnnnnnnnnsnsnN-moiety-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, and N comprises one or more nucleosides. In some embodiments, the moiety in modification pattern 4S or 5S is a lipophilic moiety. In some embodiments, the moiety in modification pattern 4S or 5S is a lipid moiety. In some embodiments, the sense strand comprises modification pattern 6S: 5′-NfsnsNfnNfnNfnNfnNfnNfnNfnNfnNfsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 7S: 5′-nsnsnnNfNfNfNfNfnnnnnnnnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 8S: 5′-nsnsnnnNfNfNfNfnnnnnnnnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 9S: 5′-nsnsnnnnNfNfNfNfnnnnnnnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 10S: 5′-NfsnsnnNfnNfnNfnNfnNfnNfnNfnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 11S: 5′-nsnsNfnNfnNfnNfnNfnNfnnnNfnNfsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 12S: 5′-NfsnsNfnNfnNfnNfnNfnnnNfnNfnNfsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 13S: 5′-nsnsnnnnNfnNfnNfnNfnNfnNfnNfsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 14S: 5′-snnnnnnNfNfNfNfnnnnnnnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 15S: 5′-snnnnNfNfNfNfNfnnnnnnnnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 16S: 5′-snnnnNfnNfNfdNnnnnnnnnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “dN” is a 2′-deoxy-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 17S: 5′-snnnnnNfNfnNfnnnnnnnnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 18S: 5′-snnnnnnNfnNfNfnnnnnnnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 19S: 5′-snnnnNfnNfnNfnNfnnnnnnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 20S: 5′-snnnnNfnNfnNfnnnnnnnnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 21S: 5′-snnnnNfNfnnNfNfnnnnnnnnnsnsn-3′ (SEQ ID NO: 2536), wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 22S: 5′-snnnnNfnnNfNfNfNfnnnnnnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 23S: 5′-snnnnnNfnNfNfnnnnnnnnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 24S: 5′-snnnnnnnNfNfNfNfnnnnnnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 25S: 5′-snnnnnNfNfNfNfNfnnnnnnnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 26S: 5′-snnnnnNfNfNfNfnnnnnnnnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 27S: 5′-snnnnnnnNfNfnNfnnnnnnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 28S: 5′-snnnnNfNfnNfNfnNfnnnnnnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 29S: 5′-snnnnnnnnNfnNfnnnnnnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 30S: 5′-snnnnNfNfnnNfnNfnnnnnnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 31S: 5′-snnnnNfNfnNfNfnnnnnnnnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 32S: 5′-snnnnnnNfNfdNNfnnnnnnnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “dN” is a 2′-deoxy-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 33S: 5′-snnnnNfnNfnNfNfnnnnnnnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “dN” is a 2′-deoxy-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 34S: 5′-snnnnNfnNfNfdNNfnnnnnnnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “dN” is a 2′-deoxy-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 35S: 5′-snnnnnnNfNfNfNfnNfnnnnnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “dN” is a 2′-deoxy-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 36S: 5′-snnnnnNfNfNfNfnNfnnnnnnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “dN” is a 2′-deoxy-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 37S: 5′-snnnnNfnNfNfdTNfnnnnnnnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “dN” is a 2′-deoxy-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 38S: 5′-snnnnNfnNfNfNfnnnnnnnnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “dN” is a 2′-deoxy-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 39S: 5′-snnnnNfnNfNfdTnnnnnnnnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “dN” is a 2′-deoxy-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 40S: 5′-snnnnNfnNfNfdNnNfnnnnnnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “dN” is a 2′-deoxy-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 42S: 5′-snnnnNfnNfNfdTnNfnnnnnnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “dN” is a 2′-deoxy-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 43S: 5′-snnnnnnNfnNfnNfnnnnnnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “dN” is a 2′-deoxy-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 44S: 5′-snnnnNfnNfNfNfNfnnnnnnnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “dN” is a 2′-deoxy-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 45S: 5′-snnnnnNfnnNfNfnnnnnnnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “dN” is a 2′-deoxy-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 46S: 5′-snnnnnnNfNfNfNfNfnnnnnnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “dN” is a 2′-deoxy-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 47S: 5′-snnnnnNfNfnNfnNfnnnnnnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “dN” is a 2′-deoxy-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 48S: 5′-nnNfnNfnNfnNfnNfnNfnnnNfnNfsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “dN” is a 2′-deoxy-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 49S: 5′-nnNfnNfnNfnNfnNfnNfnnnNfnNfsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 50S: 5′-nnnnnNfNfNfNfNfnnnnnnnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 51S: 5′-nnnnNfNfNfNfNfnnnnnnnnnnsnsn-3′), wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 52S: 5′-snnnnmnNfNfNfNfnnnnnnmnnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “dN” is a 2′-deoxy-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, “nm” is a 2′-O-methoxyethyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 53S: 5′-snnnnmnNfNfNfNfnnnnnmnnnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “dN” is a 2′-deoxy-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, “nm” is a 2′-O-methoxyethyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 54S: 5′-snnnnmnNfNfNfNfnnnnmnnnnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “dN” is a 2′-deoxy-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, “nm” is a 2′-O-methoxyethyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 55S: 5′-snnnnmnNfNfNfNfnnnmnnnnnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “dN” is a 2′-deoxy-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, “nm” is a 2′-O-methoxyethyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 56S: 5′-snnnnnmNfNfNfNfnnnmnnnnnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “dN” is a 2′-deoxy-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, “nm” is a 2′-O-methoxyethyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 57S: 5′-snnnnnmNfNfNfNfnnnnmnnnnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “dN” is a 2′-deoxy-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, “nm” is a 2′-O-methoxyethyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 58S: 5′-nnnnmnNfNfNfNfnnnnmnnnnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “dN” is a 2′-deoxy-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, “nm” is a 2′-O-methoxyethyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 59S: 5′-snsnnnnNfNfNfNfNfnnnnnnnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “dN” is a 2′-deoxy-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, “nm” is a 2′-O-methoxyethyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 60S: 5′-snnnnmnnNfNfNfNfnnnmnnnnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “dN” is a 2′-deoxy-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, “nm” is a 2′-O-methoxyethyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 61S: 5′-snnnnmNfnNfNfNfNfnnnmnnnnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “dN” is a 2′-deoxy-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, “nm” is a 2′-O-methoxyethyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 62S: 5′-snnnnmnNfNfNfNfnnnnmnnnn[i]nsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “dN” is a 2′-deoxy-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, “nm” is a 2′-O-methoxyethyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, and “[i]” is an inosine. In some embodiments, the sense strand comprises modification pattern 63S: 5′-snnnnmnNfNfNfNfnnnnmnn[i]nnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “dN” is a 2′-deoxy-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, “nm” is a 2′-O-methoxyethyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, and “[i]” is an inosine. In some embodiments, the sense strand comprises modification pattern 64S: 5′-nnnnmnnNfNfNfNfnnnmnnnnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “dN” is a 2′-deoxy-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, “nm” is a 2′-O-methoxyethyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 65S: 5′-nsnsnnmnN(C16)NfNfNfnnnnmnnnnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “dN” is a 2′-deoxy-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, “nm” is a 2′-O-methoxyethyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, and N(C16) is 2′-O-hexadecate modification. In some embodiments, N(C16) is a 2′-O-hexadecyl adenylate.

In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises modification pattern 1AS: 5′-nsNfsnNfnNfnNfnNfnnnNfnNfnNfnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 2AS: 5′-nsNfsnnnNfnNfNfnnnnNfnNfnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 3AS: 5′-nsNfsnnnNfnnnnnnnNfnNfnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 4AS: 5′-nsNfsnNfnNfnnnnnnnNfnNfnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 5AS: 5′-nsNfsnnnnnnnnnnnNfnNfnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 6AS: 5′-nsNfsnnnNfnnNfnnnnNfnNfnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 7AS: 5′-nsNfsnNfnNfnNfnNfnNfnNfnNfnNfnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 8AS: 5′-nsNfsnnnnnnnnnnnNfnnnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 9AS: 5′-nsNfsnnnNfnNfnnnnnNfnNfnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 10AS: 5′-nsNfsnNfsnNfnNfnNfnNfnNfnNfnNfnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 11AS: 5′-nsNfsnnnNfnNfnNfnnnNfnNfnNfnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “dN” is a 2′-deoxy-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 12AS: 5′-nsNfsnnnNfnNfnNfnNfnNfnNfnNfnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “dN” is a 2′-deoxy-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 13AS: 5′-nsNfsnnNfnNfnnNfnNfnNfnNfnNfnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “dN” is a 2′-deoxy-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 14AS: 5′-nsNfsnnNfnNfnNfnnnnNfnNfnNfnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “dN” is a 2′-deoxy-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 15AS: 5′-nsNfsnNfnnNfnNfnnnnNfnNfnNfnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “dN” is a 2′-deoxy-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 16AS: 5′-nsNfsnnnNfnNfnnnNfnNfnNfnNfnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “dN” is a 2′-deoxy-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 17AS: 5′-nsNfsnNfnnNfnnNfnNfnNfnNfnNfnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “dN” is a 2′-deoxy-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 18AS: 5′-nsNfsnNfnnNfnnNfnnnNfnNfnNfnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “dN” is a 2′-deoxy-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 19AS: 5′-nsNfsnnnnNfnnNfnNfnNfnNfnNfnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “dN” is a 2′-deoxy-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 20AS: 5′-nsNfsnnnnNfnNfnnNfnNfnNfnNfnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “dN” is a 2′-deoxy-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 21AS: 5′-nsNfsnnnnNfnNfnnnnNfnNfnNfnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “dN” is a 2′-deoxy-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 22AS: 5′-nsNfsnNfnNfnNfnnnnnNfnNfnNfnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “dN” is a 2′-deoxy-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the antisense strand comprises modification pattern 23AS: 5′-VPnsNfsnnnNfnNfnnnnnNfnNfnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, and VP is a 5′-vinyl phosphonate. In some embodiments, the antisense strand comprises modification pattern 24AS: 5′-VPnsNfsnNfnNfnNfnNfnNfnNfnNfnNfnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, and VP is a 5′-vinyl phosphonate. In some embodiments, the sense strand comprises modification pattern 25AS: 5′-VPnsNfsnnnNfnNfnNfnNfnNfnNfnNfnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, and VP is a 5′-vinyl phosphonate. In some embodiments, the sense strand comprises modification pattern 26AS: 5′-VPnsNfsnnNfnNfnnNfnNfnNfnNfnNfnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, and VP is a 5′-vinyl phosphonate. In some embodiments, the sense strand comprises modification pattern 27AS: 5′-VPnsNfsnNfnnNfnNfnnnnNfnNfnNfnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, and VP is a 5′-vinyl phosphonate. In some embodiments, the sense strand comprises modification pattern 28AS: 5′-nsNfsnnNfnNfnnNfnnnNfnNfnNfnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 29AS: 5′-nsNfsnnNfnNfnnNfnnnNfnNfnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 30AS: 5′-nsNfsnnnNfnNfnNfnNfnNfnNfnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 31AS: 5′-nsNfsnnNfnNfnnNfnNfnNfnNfnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 32AS: 5′-nsNfsnnnNfNfnnNfnNfnNfnNfnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 33AS: 5′-nsNfsnnNfnNfNfnNfnnnNfnNfnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 34AS: 5′-nsNfsnnNfnNfNfnnnNfnNfnNfnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 35AS: 5′-nsNfsnnnNfNfnnNfnnnNfnNfnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 36AS: 5′-nsNfsnnnnNfNfnNfnnnNfnNfnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate or phosphate linkage. In some embodiments, the sense strand comprises modification pattern 37AS: 5′-nsNfsnnNfn[NUNA]nnNfnnnNfnNfinnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, and “[NUNA]” is an unlocked nucleic acid. In some embodiments, the sense strand comprises modification pattern 38AS: 5′-nsNfsnnNf[NUNA]NfnnNfnnnNfnNfnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, and “[NUNA]” is an unlocked nucleic acid. In some embodiments, the sense strand comprises modification pattern 39AS: 5′-5VPnsNfsnnNfnNfnnNfnnnNfnNfnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, and ad VP is a 5′-vinyl phosphonate. In some embodiments, the sense strand comprises modification pattern 40AS: 5′-5VPnsNfsnnNfnNfnnNfnNfnNfnNfnnnsnsn-3′, wherein “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, “s” is a phosphorothioate or phosphate linkage, and ad VP is a 5′-vinyl phosphonate.

In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises pattern 1S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 2S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 3S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 4S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 5S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 6S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 7S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 8S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 9S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 10S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 11S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 12S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 13S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 14S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 15S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 16S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 17S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 18S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 19S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 20S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 21S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 22S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 23S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 24S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 25S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 26S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 27S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 28S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 29S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 30S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 31S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 32S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 33S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 34S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 35S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 36S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 37S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 38S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 39S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 40S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 41S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 42S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 43S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 44S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 45S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 46S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 47S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 48S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 49S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 50S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 51S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 52S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 53S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 54S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 55S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 56S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 57S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 58S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 59S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 60S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 61S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 62S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 63S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 64S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the sense strand comprises pattern 65S and the antisense strand comprises pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS.

In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, or 65S and the antisense strand comprises pattern 1AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, or 65S and the antisense strand comprises pattern 2AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, or 65S and the antisense strand comprises pattern 3AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, or 65S and the antisense strand comprises pattern 4AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, or 65S and the antisense strand comprises pattern 5AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, or 65S and the antisense strand comprises pattern 6AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, or 65S and the antisense strand comprises pattern 7AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, or 65S and the antisense strand comprises pattern 8AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, or 65S and the antisense strand comprises pattern 9AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, or 65S and the antisense strand comprises pattern 10AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, or 65S and the antisense strand comprises pattern 11AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, or 65S and the antisense strand comprises pattern 12AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, or 65S and the antisense strand comprises pattern 13AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, or 65S and the antisense strand comprises pattern 14AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, or 65S and the antisense strand comprises pattern 15AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, or 65S and the antisense strand comprises pattern 16AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, or 65S and the antisense strand comprises pattern 17AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, or 65S and the antisense strand comprises pattern 18AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, or 65S and the antisense strand comprises pattern 19AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, or 65S and the antisense strand comprises pattern 20AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, or 65S and the antisense strand comprises pattern 21AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, or 65S and the antisense strand comprises pattern 22AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, or 65S and the antisense strand comprises pattern 23AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, or 65S and the antisense strand comprises pattern 24AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, or 65S and the antisense strand comprises pattern 25AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, or 65S and the antisense strand comprises pattern 26AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, or 65S and the antisense strand comprises pattern 27AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, or 65S and the antisense strand comprises pattern 28AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, or 65S and the antisense strand comprises pattern 29AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, or 65S and the antisense strand comprises pattern 30AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, or 65S and the antisense strand comprises pattern 31AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, or 65S and the antisense strand comprises pattern 32AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, or 65S and the antisense strand comprises pattern 33AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, or 65S and the antisense strand comprises pattern 34AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, or 65S and the antisense strand comprises pattern 35AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, or 65S and the antisense strand comprises pattern 36AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, or 65S and the antisense strand comprises pattern 37AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, or 65S and the antisense strand comprises pattern 38AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, or 65S and the antisense strand comprises pattern 39AS. In some embodiments, the sense strand comprises pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, or 65S and the antisense strand comprises pattern 40AS.

In some embodiments, the sense strand comprises any one of modification patters 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, or 9S. In some embodiments, the sense strand comprises any one of modification patters 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, or 65S. In some embodiments, the sense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, or 8AS. In some embodiments, the antisense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS. In some embodiments, the antisense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, or 8AS. In some embodiments, the antisense strand comprises modification pattern 1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 44S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 58S, 59S, 60S, 61S, 62S, 63S, 64S, or 65S. In some embodiments, the sense strand or the antisense strand comprises modification pattern ASO1.

In some embodiments, purines of the sense strand comprise 2′-fluoro modified purines. In some embodiments, purines of the sense strand comprise 2′-O-methyl modified purines. In some embodiments, purines of the sense strand comprise a mixture of 2′-fluoro and 2′-O-methyl modified purines. In some embodiments, all purines of the sense strand comprise 2′-fluoro modified purines. In some embodiments, all purines of the sense strand comprise 2′-O-methyl modified purines. In some embodiments, all purines of the sense strand comprise a mixture of 2′-fluoro and 2′-O-methyl modified purines.

In some embodiments, pyrimidines of the sense strand comprise 2′-fluoro modified pyrimidines. In some embodiments, pyrimidines of the sense strand comprise 2′-O-methyl modified pyrimidines. In some embodiments, pyrimidines of the sense strand comprise a mixture of 2′-fluoro and 2′-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the sense strand comprise 2′-fluoro modified pyrimidines. In some embodiments, all pyrimidines of the sense strand comprise 2′-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the sense strand comprise a mixture of 2′-fluoro and 2′-O-methyl modified pyrimidines.

In some embodiments, purines of the sense strand comprise 2′-fluoro modified purines, and pyrimidines of the sense strand comprise a mixture of 2′-fluoro and 2′-O-methyl modified pyrimidines. In some embodiments, purines of the sense strand comprise 2′-O-methyl modified purines, and pyrimidines of the sense strand comprise a mixture of 2′-fluoro and 2′-O-methyl modified pyrimidines. In some embodiments, purines of the sense strand comprise 2′-fluoro modified purines, and pyrimidines of the sense strand comprise 2′-O-methyl modified pyrimidines. In some embodiments, purines of the sense strand comprise 2′-O-methyl modified purines, and pyrimidines of the sense strand comprise 2′-fluoro modified pyrimidines. In some embodiments, pyrimidines of the sense strand comprise 2′-fluoro modified pyrimidines, and purines of the sense strand comprise a mixture of 2′-fluoro and 2′-O-methyl modified purines. In some embodiments, pyrimidines of the sense strand comprise 2′-O-methyl modified pyrimidines, and purines of the sense strand comprise a mixture of 2′-fluoro and 2′-O-methyl modified purines. In some embodiments, pyrimidines of the sense strand comprise 2′-fluoro modified pyrimidines, and purines of the sense strand comprise 2′-O-methyl modified purines. In some embodiments, pyrimidines of the sense strand comprise 2′-O-methyl modified pyrimidines, and purines of the sense strand comprise 2′-fluoro modified purines.

In some embodiments, all purines of the sense strand comprise 2′-fluoro modified purines, and all pyrimidines of the sense strand comprise a mixture of 2′-fluoro and 2′-O-methyl modified pyrimidines. In some embodiments, all purines of the sense strand comprise 2′-O-methyl modified purines, and all pyrimidines of the sense strand comprise a mixture of 2′-fluoro and 2′-O-methyl modified pyrimidines. In some embodiments, all purines of the sense strand comprise 2′-fluoro modified purines, and all pyrimidines of the sense strand comprise 2′-O-methyl modified pyrimidines. In some embodiments, all purines of the sense strand comprise 2′-O-methyl modified purines, and all pyrimidines of the sense strand comprise 2′-fluoro modified pyrimidines. In some embodiments, all pyrimidines of the sense strand comprise 2′-fluoro modified pyrimidines, and all purines of the sense strand comprise a mixture of 2′-fluoro and 2′-O-methyl modified purines. In some embodiments, all pyrimidines of the sense strand comprise 2′-O-methyl modified pyrimidines, and all purines of the sense strand comprise a mixture of 2′-fluoro and 2′-O-methyl modified purines. In some embodiments, all pyrimidines of the sense strand comprise 2′-fluoro modified pyrimidines, and all purines of the sense strand comprise 2′-O-methyl modified purines. In some embodiments, all pyrimidines of the sense strand comprise 2′-O-methyl modified pyrimidines, and all purines of the sense strand comprise 2′-fluoro modified purines.

In some embodiments, purines of the antisense strand comprise 2′-fluoro modified purines. In some embodiments, purines of the antisense strand comprise 2′-O-methyl modified purines. In some embodiments, purines of the antisense strand comprise a mixture of 2′-fluoro and 2′-O-methyl modified purines. In some embodiments, all purines of the antisense strand comprise 2′-fluoro modified purines. In some embodiments, all purines of the antisense strand comprise 2′-O-methyl modified purines. In some embodiments, all purines of the antisense strand comprise a mixture of 2′-fluoro and 2′-O-methyl modified purines.

In some embodiments, pyrimidines of the antisense strand comprise 2′-fluoro modified pyrimidines. In some embodiments, pyrimidines of the antisense strand comprise 2′-O-methyl modified pyrimidines. In some embodiments, pyrimidines of the antisense strand comprise a mixture of 2′-fluoro and 2′-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the antisense strand comprise 2′-fluoro modified pyrimidines. In some embodiments, all pyrimidines of the antisense strand comprise 2′-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the antisense strand comprise a mixture of 2′-fluoro and 2′-O-methyl modified pyrimidines.

In some embodiments, purines of the antisense strand comprise 2′-fluoro modified purines, and pyrimidines of the antisense strand comprise a mixture of 2′-fluoro and 2′-O-methyl modified pyrimidines. In some embodiments, purines of the antisense strand comprise 2′-O-methyl modified purines, and pyrimidines of the antisense strand comprise a mixture of 2′-fluoro and 2′-O-methyl modified pyrimidines. In some embodiments, purines of the antisense strand comprise 2′-fluoro modified purines, and pyrimidines of the antisense strand comprise 2′-O-methyl modified pyrimidines. In some embodiments, purines of the antisense strand comprise 2′-O-methyl modified purines, and pyrimidines of the antisense strand comprise 2′-fluoro modified pyrimidines. In some embodiments, pyrimidines of the antisense strand comprise 2′-fluoro modified pyrimidines, and purines of the antisense strand comprise a mixture of 2′-fluoro and 2′-O-methyl modified purines. In some embodiments, pyrimidines of the antisense strand comprise 2′-O-methyl modified pyrimidines, and purines of the antisense strand comprise a mixture of 2′-fluoro and 2′-O-methyl modified purines. In some embodiments, pyrimidines of the antisense strand comprise 2′-fluoro modified pyrimidines, and purines of the antisense strand comprise 2′-O-methyl modified purines. In some embodiments, pyrimidines of the antisense strand comprise 2′-O-methyl modified pyrimidines, and purines of the antisense strand comprise 2′-fluoro modified purines.

In some embodiments, all purines of the antisense strand comprise 2′-fluoro modified purines, and all pyrimidines of the antisense strand comprise a mixture of 2′-fluoro and 2′-O-methyl modified pyrimidines. In some embodiments, all purines of the antisense strand comprise 2′-O-methyl modified purines, and all pyrimidines of the antisense strand comprise a mixture of 2′-fluoro and 2′-O-methyl modified pyrimidines. In some embodiments, all purines of the antisense strand comprise 2′-fluoro modified purines, and all pyrimidines of the antisense strand comprise 2′-O-methyl modified pyrimidines. In some embodiments, all purines of the antisense strand comprise 2′-O-methyl modified purines, and all pyrimidines of the antisense strand comprise 2′-fluoro modified pyrimidines. In some embodiments, all pyrimidines of the antisense strand comprise 2′-fluoro modified pyrimidines, and all purines of the antisense strand comprise a mixture of 2′-fluoro and 2′-O-methyl modified purines. In some embodiments, all pyrimidines of the antisense strand comprise 2′-O-methyl modified pyrimidines, and all purines of the antisense strand comprise a mixture of 2′-fluoro and 2′-O-methyl modified purines. In some embodiments, all pyrimidines of the antisense strand comprise 2′-fluoro modified pyrimidines, and all purines of the antisense strand comprise 2′-O-methyl modified purines. In some embodiments, all pyrimidines of the antisense strand comprise 2′-O-methyl modified pyrimidines, and all purines of the antisense strand comprise 2′-fluoro modified purines.

Disclosed herein, in some embodiments, are modified oligonucleotides. The modified oligonucleotide may be an siRNA that includes modifications to the ribose rings, and phosphate linkages. The modifications may be in particular patterns that maximize cell delivery, stability, and efficiency. The siRNA may also include a vinyl phosphonate and a hydrophobic group. These modifications may aid in delivery to a cell or tissue within a subject. The modified oligonucleotide may be used in a method such as a treatment method or a method of reducing gene expression.

In some embodiments, the oligonucleotide comprises a duplex consisting of 21 nucleotide single strands with base pairing between 19 of the base pairs. In some embodiments, the duplex comprises single-stranded 2 nucleotide overhangs are at the 3′ ends of each strand. One strand (antisense strand) is complementary to a MTRES1 mRNA. Each end of the antisense strand has one to two phosphorothioate bonds. The 5′ end has an optional phosphate mimic such as a vinyl phosphonate. In some embodiments, the oligonucleotide is used to knock down a MTRES1 mRNA or a target protein. In some embodiments, the sense strand has the same sequence as the MTRES1 mRNA. In some embodiments, there are 1-2 phosphorothioates at the 3′ end. In some embodiments, there are 1 or no phosphorothioates at the 5′ end. In some embodiments, there is a hydrophobic conjugate of 12 to 25 carbons attached at the 5′ end via a phosphodiester bond.

In some cases, the sense strand of any of the siRNAs comprises siRNA with a particular modification pattern. In some embodiments of the modification pattern, position 9 counting from the 5′ end of the sense strand may have a 2′F modification. In some embodiments, when position 9 of the sense strand is a pyrimidine, then all purines in the sense strand have a 2′OMe modification. In some embodiments, when position 9 is the only pyrimidine between positions 5 and 11 of the sense stand, then position 9 is the only position with a 2′F modification in the sense strand. In some embodiments, when position 9 and only one other base between positions 5 and 11 of the sense strand are pyrimidines, then both of these pyrimidines are the only two positions with a 2′F modification in the sense strand. In some embodiments, when position 9 and only two other bases between positions 5 and 11 of the sense strand are pyrimidines, and those two other pyrimidines are in adjacent positions so that there would be not three 2′F modifications in a row, then any combination of 2′F modifications can be made that give three 2′F modifications in total. In some embodiments, when there are more than 2 pyrimidines between positions 5 and 11 of the sense strand, then all combinations of pyrimidines having the 2′F modification are allowed that have three to five 2′F modifications in total, provided that the sense strand does not have three 2′F modifications in a row. In some cases, the sense strand of any of the siRNAs comprises a modification pattern which conforms to any or all of these sense strand rules.

In some embodiments, when position 9 of the sense strand is a purine, then all purines in the sense strand have a 2′OMe modification. In some embodiments, when position 9 is the only purine between positions 5 and 11 of the sense stand, then position 9 is the only position with a 2′F modification in the sense strand. In some embodiments, when position 9 and only one other base between positions 5 and 11 of the sense strand are purines, then both of these purines are the only two positions with a 2′F modification in the sense strand. In some embodiments, when position 9 and only two other bases between positions 5 and 11 of the sense strand are purines, and those two other purines are in adjacent positions so that there would be not three 2′F modifications in a row, then any combination of 2′F modifications can be made that give three 2′F modifications in total. In some embodiments, when there are more than 2 purines between positions 5 and 11 of the sense strand, then all combinations of purines having the 2′F modification are allowed that have three to five 2′F modifications in total, provided that the sense strand does not have three 2′F modifications in a row. In some cases, the sense strand of any of the siRNAs comprises a modification pattern which conforms to any or all of these sense strand rules.

In some cases, position 9 of the sense strand can be a 2′deoxy. In these cases, 2′F and 2′OMe modifications may occur at the other positions of the sense strand. In some cases, the sense strand of any of the siRNAs comprises a modification pattern which conforms to these sense strand rules.

In some cases, the sense strand of any of the siRNAs comprises a modification pattern which conforms to these sense strand rules.

Terminal modifications useful for modulating activity include modification of the 5′ end of the antisense strand with phosphate or phosphate analogs. In certain embodiments, the 5′ end of the antisense strand is phosphorylated or includes a phosphoryl analog. Exemplary 5′-phosphate modifications include those which are compatible with RNA-induced silencing complex (RISC) mediated gene silencing. In some embodiments, the 3′ end of the antisense strand is phosphorylated or includes a phosphoryl analog. In some embodiments, the 5′ end of the sense strand is phosphorylated or includes a phosphoryl analog. In some embodiments, the 3′ end of the sense strand is phosphorylated or includes a phosphoryl analog.

In some embodiments, the oligonucleotide comprises a phosphate or phosphate mimic at the 5′ end of the antisense strand. In some embodiment, the phosphate mimic includes a 5′-vinyl phosphonate (VP). In some embodiment, the phosphate mimic is a 5′-VP. In some embodiments, the oligonucleotide comprises a phosphate or phosphate mimic at the 3′ end of the antisense strand. In some embodiments, the oligonucleotide comprises a phosphate or phosphate mimic at the 5′ end of the sense strand. In some embodiments, the oligonucleotide comprises a phosphate or phosphate mimic at the 3′ end of the sense strand.

Disclosed herein, in some embodiments are compositions comprising an oligonucleotide that targets MTRES1 and when administered to a cell decreases expression of MTRES1, wherein the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand, wherein the sense strand comprises a sense strand sequence described herein in which at least one internucleoside linkage is modified and at least one nucleoside is modified, or an sense strand sequence comprising 1 or 2 nucleoside substitutions, additions, or deletions of the oligonucleotide sequence in which at least one internucleoside linkage is modified and at least one nucleoside is modified, and wherein the antisense strand comprises an antisense strand sequence described herein in which at least one internucleoside linkage is modified and at least one nucleoside is modified, or an oligonucleotide sequence comprising 1 or 2 nucleoside substitutions, additions, or deletions of the antisense strand sequence in which at least one internucleoside linkage is modified and at least one nucleoside is modified. Some embodiments relate to methods that include administering the composition to a subject.

In some embodiments, the siRNA comprises a sense strand, an antisense strand, and a lipid moiety connected to an end of the sense or antisense strand; wherein the lipid moiety comprises a phenyl or cyclohexanyl linker, wherein the linker is connected to a lipid and to the end of the sense or antisense strand. In some embodiments, any one of the following is true with regard to the sense strand: (a) all purines comprise fluoro modified purines and all pyrimidines comprise (i) a mixture of 2′-O-methyl and 2′-O-methoxyethyl modified pyrimidines; or (ii) a mixture of 2′-fluoro, 2′-O-methyl, and 2′-O-methoxyethyl modified pyrimidines; (b) all purines comprise 2′-O-methyl modified purines and all pyrimidines comprise (vi) all pyrimidines of the sense strand comprise a mixture of 2′-fluoro and 2′-O-methoxyethyl modified pyrimidines; or (ii) a mixture of 2′-fluoro, 2′-O-methyl, and 2′-O-methoxyethyl modified pyrimidines; (c) all purines comprise 2′-O-methoxyethyl modified purines and all pyrimidines comprise (i) a mixture of 2′-fluoro and 2′-O-methyl modified pyrimidines; or (ii) a mixture of 2′-fluoro, 2′-O-methyl, and 2′-O-methoxyethyl modified pyrimidines; (d) all purines comprise a mixture of 2′-fluoro and 2′-O-methyl modified purines and all pyrimidines comprise (i) 2′-O-methoxyethyl modified pyrimidines; (ii) a mixture of 2′-O-methyl and 2′-O-methoxyethyl modified pyrimidines; (iii) a mixture of 2′-fluoro and 2′-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2′-fluoro, 2′-O-methyl, and 2′-O-methoxyethyl modified pyrimidines; (e) all purines comprise a mixture of 2′-fluoro and 2′-O-methoxyethyl modified purines and all pyrimidines of the sense strand comprise (i) 2′-O-methyl modified pyrimidines; (ii) a mixture of 2′-fluoro and 2′-O-methyl modified pyrimidines; (iii) a mixture of 2′-O-methyl and 2′-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2′-fluoro, 2′-O-methyl, and 2′-O-methoxyethyl modified pyrimidines; (f) all purines comprise a mixture of 2′-O-methyl and 2′-O-methoxyethyl modified purines and all pyrimidines comprise (i) 2′-fluoro modified pyrimidines; (ii) a mixture of 2′-fluoro and 2′-O-methyl modified pyrimidines; (iii) a mixture of 2′-fluoro and 2′-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2′-fluoro, 2′-O-methyl, and 2′-O-methoxyethyl modified pyrimidines; or (g) all purines comprise a mixture of 2′-fluoro, 2′-O-methyl, and 2′-O-methoxyethyl modified purines and all pyrimidines comprise (i) 2′-fluoro modified pyrimidines; (ii) 2′-O-methyl modified pyrimidines; (iii) 2′-O-methoxyethyl modified pyrimidines; (iv) a mixture of 2′-fluoro and 2′-O-methyl modified pyrimidines; (v) a mixture of 2′-O-methyl and 2′-O-methoxyethyl modified pyrimidines; (vi) a mixture of 2′-fluoro and 2′-O-methoxyethyl modified pyrimidines; or (vii) a mixture of 2′-fluoro, 2′-O-methyl, and 2′-O-methoxyethyl modified pyrimidines. In some embodiments, any one of the following is true with regard to the antisense strand: all purines comprise 2′-fluoro modified purines, and all pyrimidines comprise a mixture of 2′-fluoro and 2′-O-methyl modified pyrimidines; all purines comprise 2′-O-methyl modified purines, and all pyrimidines comprise a mixture of 2′-fluoro and 2′-O-methyl modified pyrimidines; all purines comprise 2′-O-methyl modified purines, and all pyrimidines comprise 2′-fluoro modified pyrimidines; all pyrimidines comprise 2′-fluoro modified pyrimidines, and all purines comprise a mixture of 2′-fluoro and 2′-O-methyl modified purines; all pyrimidines comprise 2′-O-methyl modified pyrimidines, and all purines comprise a mixture of 2′-fluoro and 2′-O-methyl modified purines; or all pyrimidines comprise 2′-O-methyl modified pyrimidines, and all purines comprise 2′-fluoro modified purines. In some embodiments, the siRNA comprises comprising a sense strand and an antisense strand; wherein the antisense strand comprises a 5′ end comprising a vinyl phosphonate and 2 phosphorothioate linkages, and a 3′ end comprising 2 phosphorothioate linkages; wherein the sense strand comprises (a) all purines comprise fluoro modified purines and all pyrimidines comprise (i) a mixture of 2′-O-methyl and 2′-O-methoxyethyl modified pyrimidines; or (ii) a mixture of 2′-fluoro, 2′-O-methyl, and 2′-O-methoxyethyl modified pyrimidines; (b) all purines comprise 2′-O-methyl modified purines and all pyrimidines comprise (vi) all pyrimidines of the sense strand comprise a mixture of 2′-fluoro and 2′-O-methoxyethyl modified pyrimidines; or (ii) a mixture of 2′-fluoro, 2′-O-methyl, and 2′-O-methoxyethyl modified pyrimidines; (c) all purines comprise 2′-O-methoxyethyl modified purines and all pyrimidines comprise (i) a mixture of 2′-fluoro and 2′-O-methyl modified pyrimidines; or (ii) a mixture of 2′-fluoro, 2′-O-methyl, and 2′-O-methoxyethyl modified pyrimidines; (d) all purines comprise a mixture of 2′-fluoro and 2′-O-methyl modified purines and all pyrimidines comprise (i) 2′-O-methoxyethyl modified pyrimidines; (ii) a mixture of 2′-O-methyl and 2′-O-methoxyethyl modified pyrimidines; (iii) a mixture of 2′-fluoro and 2′-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2′-fluoro, 2′-O-methyl, and 2′-O-methoxyethyl modified pyrimidines; (e) all purines comprise a mixture of 2′-fluoro and 2′-O-methoxyethyl modified purines and all pyrimidines of the sense strand comprise (i) 2′-O-methyl modified pyrimidines; (ii) a mixture of 2′-fluoro and 2′-O-methyl modified pyrimidines; (iii) a mixture of 2′-O-methyl and 2′-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2′-fluoro, 2′-O-methyl, and 2′-O-methoxyethyl modified pyrimidines; (f) all purines comprise a mixture of 2′-O-methyl and 2′-O-methoxyethyl modified purines and all pyrimidines comprise (i) 2′-fluoro modified pyrimidines; (ii) a mixture of 2′-fluoro and 2′-O-methyl modified pyrimidines; (iii) a mixture of 2′-fluoro and 2′-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2′-fluoro, 2′-O-methyl, and 2′-O-methoxyethyl modified pyrimidines; or (g) all purines comprise a mixture of 2′-fluoro, 2′-O-methyl, and 2′-O-methoxyethyl modified purines and all pyrimidines comprise (i) 2′-fluoro modified pyrimidines; (ii) 2′-O-methyl modified pyrimidines; (iii) 2′-O-methoxyethyl modified pyrimidines; (iv) a mixture of 2′-fluoro and 2′-O-methyl modified pyrimidines; (v) a mixture of 2′-O-methyl and 2′-O-methoxyethyl modified pyrimidines; (vi) a mixture of 2′-fluoro and 2′-O-methoxyethyl modified pyrimidines; or (vii) a mixture of 2′-fluoro, 2′-O-methyl, and 2′-O-methoxyethyl modified pyrimidines; and wherein any one of the following is true with regard to the antisense strand: all purines comprise 2′-fluoro modified purines, and all pyrimidines comprise a mixture of 2′-fluoro and 2′-O-methyl modified pyrimidines, all purines comprise 2′-O-methyl modified purines, and all pyrimidines comprise a mixture of 2′-fluoro and 2′-O-methyl modified pyrimidines, all purines comprise 2′-O-methyl modified purines, and all pyrimidines comprise 2′-fluoro modified pyrimidines, all pyrimidines comprise 2′-fluoro modified pyrimidines, and all purines comprise a mixture of 2′-fluoro and 2′-O-methyl modified purines, all pyrimidines comprise 2′-O-methyl modified pyrimidines, and all purines comprise a mixture of 2′-fluoro and 2′-O-methyl modified purines, or all pyrimidines comprise 2′-O-methyl modified pyrimidines, and all purines comprise 2′-fluoro modified purines.

In some embodiments, any one of the following is true with regard to the sense strand: (a) all purines comprise fluoro modified purines and all pyrimidines comprise (i) a mixture of 2′-O-methyl and 2′-O-methoxyethyl modified pyrimidines; or (ii) a mixture of 2′-fluoro, 2′-O-methyl, and 2′-O-methoxyethyl modified pyrimidines; (b) all purines comprise 2′-O-methyl modified purines and all pyrimidines comprise (vi) all pyrimidines of the sense strand comprise a mixture of 2′-fluoro and 2′-O-methoxyethyl modified pyrimidines; or (ii) a mixture of 2′-fluoro, 2′-O-methyl, and 2′-O-methoxyethyl modified pyrimidines; (c) all purines comprise 2′-O-methoxyethyl modified purines and all pyrimidines comprise (i) a mixture of 2′-fluoro and 2′-O-methyl modified pyrimidines; or (ii) a mixture of 2′-fluoro, 2′-O-methyl, and 2′-O-methoxyethyl modified pyrimidines; (d) all purines comprise a mixture of 2′-fluoro and 2′-O-methyl modified purines and all pyrimidines comprise (i) 2′-O-methoxyethyl modified pyrimidines; (ii) a mixture of 2′-O-methyl and 2′-O-methoxyethyl modified pyrimidines; (iii) a mixture of 2′-fluoro and 2′-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2′-fluoro, 2′-O-methyl, and 2′-O-methoxyethyl modified pyrimidines; (e) all purines comprise a mixture of 2′-fluoro and 2′-O-methoxyethyl modified purines and all pyrimidines of the sense strand comprise (i) 2′-O-methyl modified pyrimidines; (ii) a mixture of 2′-fluoro and 2′-O-methyl modified pyrimidines; (iii) a mixture of 2′-O-methyl and 2′-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2′-fluoro, 2′-O-methyl, and 2′-O-methoxyethyl modified pyrimidines; (f) all purines comprise a mixture of 2′-O-methyl and 2′-O-methoxyethyl modified purines and all pyrimidines comprise (i) 2′-fluoro modified pyrimidines; (ii) a mixture of 2′-fluoro and 2′-O-methyl modified pyrimidines; (iii) a mixture of 2′-fluoro and 2′-O-methoxyethyl modified pyrimidines; or (iv) a mixture of 2′-fluoro, 2′-O-methyl, and 2′-O-methoxyethyl modified pyrimidines; or (g) all purines comprise a mixture of 2′-fluoro, 2′-O-methyl, and 2′-O-methoxyethyl modified purines and all pyrimidines comprise (i) 2′-fluoro modified pyrimidines; (ii) 2′-O-methyl modified pyrimidines; (iii) 2′-O-methoxyethyl modified pyrimidines; (iv) a mixture of 2′-fluoro and 2′-O-methyl modified pyrimidines; (v) a mixture of 2′-O-methyl and 2′-O-methoxyethyl modified pyrimidines; (vi) a mixture of 2′-fluoro and 2′-O-methoxyethyl modified pyrimidines; or (vii) a mixture of 2′-fluoro, 2′-O-methyl, and 2′-O-methoxyethyl modified pyrimidines. In some embodiments, a deoxy nucleoside may be included in the sense strand. In some embodiments, the sense strand includes the deoxy nucleoside. The deoxy nucleoside may be at nucleoside position 9 of the sense strand. In some embodiments, the sense strand does not include a deoxy nucleoside. The deoxy nucleoside of the sense strand may be otherwise unmodified.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 9, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 9, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 9. The siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 9. The siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 9. The siRNA may include some unmodified internucleoside linkages or nucleosides.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 10, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 10, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 10. The siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 10. The siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 10. The siRNA may include some unmodified internucleoside linkages or nucleosides.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 12A, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 12A, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 12A. The siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 12A. The siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 12A. The siRNA may include some unmodified internucleoside linkages or nucleosides.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 14A, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 14A, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 14A. The siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 14A. The siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 14A. The siRNA may include some unmodified internucleoside linkages or nucleosides.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 16A, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 16A, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 16A. The siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 16A. The siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 16A. The siRNA may include some unmodified internucleoside linkages or nucleosides.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 23, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 23, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 23. The siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 23. The siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 23. The siRNA may include some unmodified internucleoside linkages or nucleosides.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 27, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 27, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 27. The siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 27. The siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 27. The siRNA may include some unmodified internucleoside linkages or nucleosides.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 27, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 27, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 27. The siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 27. The siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 27. The siRNA may include some unmodified internucleoside linkages or nucleosides.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 30, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 30, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 30. The siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 30. The siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 30. The siRNA may include some unmodified internucleoside linkages or nucleosides.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 33, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 33, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 33. The siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 33. The siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 33. The siRNA may include some unmodified internucleoside linkages or nucleosides.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 36, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 36, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 36. The siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 36. The siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 36. The siRNA may include some unmodified internucleoside linkages or nucleosides.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 39, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 39, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 39. The siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 39. The siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 39. The siRNA may include some unmodified internucleoside linkages or nucleosides.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 41, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 41, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 41. The siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 41. The siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 41. The siRNA may include some unmodified internucleoside linkages or nucleosides.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 49, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 49, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 49. The siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 49. The siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 49. The siRNA may include some unmodified internucleoside linkages or nucleosides.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 52A, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 52A, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 52A. The siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 52A. The siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 52A. The siRNA may include some unmodified internucleoside linkages or nucleosides.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 54A, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 54A, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 54A. The siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 54A. The siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 54A. The siRNA may include some unmodified internucleoside linkages or nucleosides.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 56, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 56, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 56. The siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 56. The siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 56. The siRNA may include some unmodified internucleoside linkages or nucleosides.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 59, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 59, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 59. The siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 59. The siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 59. The siRNA may include some unmodified internucleoside linkages or nucleosides.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 62A, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 62A, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 62A. The siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 62A. The siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 62A. The siRNA may include some unmodified internucleoside linkages or nucleosides.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 64A, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 64A, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 64A. The siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 64A. The siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 64A. The siRNA may include some unmodified internucleoside linkages or nucleosides

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 67A, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 67A, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 67A. The siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 67A. The siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 67A. The siRNA may include some unmodified internucleoside linkages or nucleosides.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 68, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 68, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 68. The siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 68. The siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 68. The siRNA may include some unmodified internucleoside linkages or nucleosides.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 71, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 71, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 71. The siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 71. The siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 71. The siRNA may include some unmodified internucleoside linkages or nucleosides.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 74, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 74, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 74. The siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 74. The siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 74. The siRNA may include some unmodified internucleoside linkages or nucleosides.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 77, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 77, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 77. The siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 77. The siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 77. The siRNA may include some unmodified internucleoside linkages or nucleosides.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 80, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 80, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 80. The siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 80. The siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 80. The siRNA may include some unmodified internucleoside linkages or nucleosides.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 83, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 83, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 83. The siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 83. The siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 83. The siRNA may include some unmodified internucleoside linkages or nucleosides.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 86, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 86, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 86. The siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 86. The siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 86. The siRNA may include some unmodified internucleoside linkages or nucleosides.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 89, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 89, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 89. The siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 89. The siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 89. The siRNA may include some unmodified internucleoside linkages or nucleosides.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 92, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 92, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 92. The siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 92. The siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 92. The siRNA may include some unmodified internucleoside linkages or nucleosides.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 95, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 95, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 95. The siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 95. The siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 95. The siRNA may include some unmodified internucleoside linkages or nucleosides.

In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 98, or a nucleic acid sequence thereof having 3 or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 98, or a nucleic acid sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the siRNA comprises the sense strand and/or the antisense strand sequence of an siRNA in Table 98. The siRNA may include the same internucleoside linkage modifications or nucleoside modifications as those in Table 98. The siRNA may include any different internucleoside linkage modifications or nucleoside modifications different from those in Table 92. The siRNA may include some unmodified internucleoside linkages or nucleosides.

In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with SEQ ID NO: 3296-3299. In some embodiments, the sense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 3296-3299, at least 80% identical to SEQ ID NO: 3296-3299, at least 85% identical to SEQ ID NO: 3296-3299, at least 90% identical to SEQ ID NO: 3296-3299, or at least 95% identical to SEQ ID NO: 3296-3299. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 3296-3299, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 3296-3299, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 3296-3299. The sense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety.

In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with SEQ ID NO: 3305-3318 or 3339. In some embodiments, the sense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 3305-3318 or 3339, at least 80% identical to SEQ ID NO: 3305-3318 or 3339, at least 85% identical to SEQ ID NO: 3305-3318 or 3339, at least 90% identical to SEQ ID NO: 3305-3318 or 3339, or at least 95% identical to SEQ ID NO: 3305-3318 or 3339. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 3305-3318 or 3339, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 3305-3318 or 3339, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 3305-3318 or 3339. The sense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety.

In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with SEQ ID NO: 2472. In some embodiments, the sense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 2472, at least 80% identical to SEQ ID NO: 2472, at least 85% identical to SEQ ID NO: 2472, at least 90% identical to SEQ ID NO: 2472, or at least 95% identical to SEQ ID NO: 2472. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 2472, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 2472, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 2472. The sense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety. In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with SEQ ID NO: 2489. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 2489, at least 80% identical to SEQ ID NO: 2489, at least 85% identical to SEQ ID NO: 2489, at least 90% identical to SEQ ID NO: 2489, or at least 95% identical to SEQ ID NO: 2489. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 2489, or an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 2489, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 2489. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety.

In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with SEQ ID NO: 2478. In some embodiments, the sense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 2478, at least 80% identical to SEQ ID NO: 2478, at least 85% identical to SEQ ID NO: 2478, at least 90% identical to SEQ ID NO: 2478, or at least 95% identical to SEQ ID NO: 2478. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 2478, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 2478, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 2478. The sense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety. In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with SEQ ID NO: 2495. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 2495, at least 80% identical to SEQ ID NO: 2495, at least 85% identical to SEQ ID NO: 2495, at least 90% identical to SEQ ID NO: 2495, or at least 95% identical to SEQ ID NO: 2495. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 2495, or an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 2495, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 2495. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety.

In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with SEQ ID NO: 2479. In some embodiments, the sense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 2479, at least 80% identical to SEQ ID NO: 2479, at least 85% identical to SEQ ID NO: 2479, at least 90% identical to SEQ ID NO: 2479, or at least 95% identical to SEQ ID NO: 2479. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 2479, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 2479, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 2479. The sense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety. In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with SEQ ID NO: 2496. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 2496, at least 80% identical to SEQ ID NO: 2496, at least 85% identical to SEQ ID NO: 2496, at least 90% identical to SEQ ID NO: 2496, or at least 95% identical to SEQ ID NO: 2496. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 2496, or an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 2496, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 2496. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety.

In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with SEQ ID NO: 2480. In some embodiments, the sense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 2480, at least 80% identical to SEQ ID NO: 2480, at least 85% identical to SEQ ID NO: 2480, at least 90% identical to SEQ ID NO: 2480, or at least 95% identical to SEQ ID NO: 2480. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 2480, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 2480, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 2480. The sense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety. In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with SEQ ID NO: 2497. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 2497, at least 80% identical to SEQ ID NO: 2497, at least 85% identical to SEQ ID NO: 2497, at least 90% identical to SEQ ID NO: 2497, or at least 95% identical to SEQ ID NO: 2497. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 2497, or an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 2497, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 2497. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety.

In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with SEQ ID NO: 2507. In some embodiments, the sense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 2507, at least 80% identical to SEQ ID NO: 2507, at least 85% identical to SEQ ID NO: 2507, at least 90% identical to SEQ ID NO: 2507, or at least 95% identical to SEQ ID NO: 2507. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 2507, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 2507, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 2507. The sense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety. In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with SEQ ID NO: 2517. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 2517, at least 80% identical to SEQ ID NO: 2517, at least 85% identical to SEQ ID NO: 2517, at least 90% identical to SEQ ID NO: 2517, or at least 95% identical to SEQ ID NO: 2517. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 2517, or an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 2517, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 2517. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety.

In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with SEQ ID NO: 3239. In some embodiments, the sense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 3239, at least 80% identical to SEQ ID NO: 3239, at least 85% identical to SEQ ID NO: 3239, at least 90% identical to SEQ ID NO: 3239, or at least 95% identical to SEQ ID NO: 3239. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 3239, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 3239, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 3239. The sense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety.

In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with SEQ ID NO: 3241. In some embodiments, the sense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 3241, at least 80% identical to SEQ ID NO: 3241, at least 85% identical to SEQ ID NO: 3241, at least 90% identical to SEQ ID NO: 3241, or at least 95% identical to SEQ ID NO: 3241. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 3241, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 3241, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 3241. The sense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety.

In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with SEQ ID NO: 3242. In some embodiments, the sense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 3242, at least 80% identical to SEQ ID NO: 3242, at least 85% identical to SEQ ID NO: 3242, at least 90% identical to SEQ ID NO: 3242, or at least 95% identical to SEQ ID NO: 3242. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 3242, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 3242, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 3242. The sense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety.

In some embodiments, the siRNA comprises a sense strand having a sequence in accordance with SEQ ID NO: 3270. In some embodiments, the sense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 3270, at least 80% identical to SEQ ID NO: 3270, at least 85% identical to SEQ ID NO: 3270, at least 90% identical to SEQ ID NO: 3270, or at least 95% identical to SEQ ID NO: 3270. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 3270, or a sense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of the sequence of SEQ ID NO: 3270, or a sense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the sense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 3270. The sense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety.

In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with SEQ ID NO: 3300-3304. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 3300-3304, at least 80% identical to SEQ ID NO: 3300-3304, at least 85% identical to SEQ ID NO: 3300-3304, at least 90% identical to SEQ ID NO: 3300-3304, or at least 95% identical to SEQ ID NO: 3300-3304. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 3300-3304, or an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 3300-3304, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 3300-3304. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety. The antisense strand may comprise a 5′-vinyl phosphonate (VP).

In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with SEQ ID NO: 3319-3337 or 3340. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 3319-3337 or 3340, at least 80% identical to SEQ ID NO: 3319-3337 or 3340, at least 85% identical to SEQ ID NO: 3319-3337 or 3340, at least 90% identical to SEQ ID NO: 3319-3337 or 3340, or at least 95% identical to SEQ ID NO: 3319-3337 or 3340. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 3319-3337 or 3340, or an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 3319-3337 or 3340, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 3319-3337 or 3340. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety. The antisense strand may comprise a 5′-vinyl phosphonate (VP).

In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with SEQ ID NO: 2468. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 2468, at least 80% identical to SEQ ID NO: 2468, at least 85% identical to SEQ ID NO: 2468, at least 90% identical to SEQ ID NO: 2468, or at least 95% identical to SEQ ID NO: 2468. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 2468, or an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 2468, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 2468. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety. The antisense strand may comprise a 5′-vinyl phosphonate (VP).

In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with SEQ ID NO: 3243. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 3243, at least 80% identical to SEQ ID NO: 3243, at least 85% identical to SEQ ID NO: 3243, at least 90% identical to SEQ ID NO: 3243, or at least 95% identical to SEQ ID NO: 3243. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 3243, or an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 3243, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 3243. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety. The antisense strand may comprise a 5′-vinyl phosphonate (VP).

In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with SEQ ID NO: 3244. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 3244, at least 80% identical to SEQ ID NO: 3244, at least 85% identical to SEQ ID NO: 3244, at least 90% identical to SEQ ID NO: 3244, or at least 95% identical to SEQ ID NO: 3244. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 3244, or an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 3244, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 3244. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety. The antisense strand may comprise a 5′-vinyl phosphonate (VP).

In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with SEQ ID NO: 3245. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 3245, at least 80% identical to SEQ ID NO: 3245, at least 85% identical to SEQ ID NO: 3245, at least 90% identical to SEQ ID NO: 3245, or at least 95% identical to SEQ ID NO: 3245. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 3245, or an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 3245, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 3245. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety. The antisense strand may comprise a 5′-vinyl phosphonate (VP).

In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with SEQ ID NO: 3246. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 3246, at least 80% identical to SEQ ID NO: 3246, at least 85% identical to SEQ ID NO: 3246, at least 90% identical to SEQ ID NO: 3246, or at least 95% identical to SEQ ID NO: 3246. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 3246, or an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 3246, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 3246. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety. The antisense strand may comprise a 5′-vinyl phosphonate (VP).

In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with SEQ ID NO: 3247. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 3247, at least 80% identical to SEQ ID NO: 3247, at least 85% identical to SEQ ID NO: 3247, at least 90% identical to SEQ ID NO: 3247, or at least 95% identical to SEQ ID NO: 3247. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 3247, or an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 3247, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 3247. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety. The antisense strand may comprise a 5′-vinyl phosphonate (VP).

In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with SEQ ID NO: 3248. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 3248, at least 80% identical to SEQ ID NO: 3248, at least 85% identical to SEQ ID NO: 3248, at least 90% identical to SEQ ID NO: 3248, or at least 95% identical to SEQ ID NO: 3248. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 3248, or an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 3248, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 3248. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety. The antisense strand may comprise a 5′-vinyl phosphonate (VP).

In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with SEQ ID NO: 3249. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 3249, at least 80% identical to SEQ ID NO: 3249, at least 85% identical to SEQ ID NO: 3249, at least 90% identical to SEQ ID NO: 3249, or at least 95% identical to SEQ ID NO: 3249. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 3249, or an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 3249, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 3249. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety. The antisense strand may comprise a 5′-vinyl phosphonate (VP).

In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with SEQ ID NO: 3250. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 3250, at least 80% identical to SEQ ID NO: 3250, at least 85% identical to SEQ ID NO: 3250, at least 90% identical to SEQ ID NO: 3250, or at least 95% identical to SEQ ID NO: 3250. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 3250, or an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 3250, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 3250. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety. The antisense strand may comprise a 5′-vinyl phosphonate (VP).

In some embodiments, the siRNA comprises an antisense strand having a sequence in accordance with SEQ ID NO: 3277. In some embodiments, the antisense strand sequence comprises or consists of sequence at least 75% identical to SEQ ID NO: 3277, at least 80% identical to SEQ ID NO: 3277, at least 85% identical to SEQ ID NO: 3277, at least 90% identical to SEQ ID NO: 3277, or at least 95% identical to SEQ ID NO: 3277. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 3277, or an antisense strand sequence thereof having 1, 2, 3, or 4 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of the sequence of SEQ ID NO: 3277, or an antisense strand sequence thereof having 1 or 2 nucleoside substitutions, additions, or deletions. In some embodiments, the antisense strand sequence comprises or consists of a sequence 100% identical to SEQ ID NO: 3277. The antisense strand may comprise a moiety such as a GalNAc moiety or a lipid moiety. The antisense strand may comprise a 5′-vinyl phosphonate (VP).

In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises an antisense oligonucleotide (ASO). In some embodiments, the ASO comprises modification pattern ASO1: 5′-nsnsnsnsnsdNsdNsdNsdNsdNsdNsdNsdNsdNsdNsnsnsnsnsn-3′ (SEQ ID NO: 2461), wherein “dN” is any deoxynucleotide, “n” is a 2′-O-methyl or 2′-O-methoxyethyl-modified nucleoside, and “s” is a phosphorothioate linkage. In some embodiments, the ASO comprises modification pattern 1S1S, 2S, 3S, 4S, 5S, 6S, 7S, 8S, 9S, 10S, 11S, 12S, 13S, 14S, 15S, 16S, 17S, 18S, 19S, 20S, 21S, 22S, 23S, 24S, 25S, 26S, 27S, 28S, 29S, 30S, 31S, 32S, 33S, 34S, 35S, 36S, 37S, 38S, 39S, 40S, 41S, 42S, 43S, 44S, 45S, 45S, 46S, 47S, 48S, 49S, 50S, 51S, 52S, 53S, 54S, 55S, 56S, 57S, 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, 9AS, 10AS, 11AS, 12AS, 13AS, 14AS, 15AS, 16AS, 17AS, 18AS, 19AS, 20AS, 21AS, 22AS, 23AS, 24AS, 25AS, 26AS, 27AS, 28AS, 29AS, 30AS, 31AS, 32AS, 34AS, 35AS, 36AS, 37AS, 38AS, 39AS, or 40AS.

In some embodiments, the composition is a pharmaceutical composition. In some embodiments, the composition is sterile. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

In some embodiments, the pharmaceutically acceptable carrier comprises water. In some embodiments, the pharmaceutically acceptable carrier comprises a buffer. In some embodiments, the pharmaceutically acceptable carrier comprises a saline solution. In some embodiments, the pharmaceutically acceptable carrier comprises water, a buffer, or a saline solution. In some embodiments, the composition comprises a liposome. In some embodiments, the pharmaceutically acceptable carrier comprises liposomes, lipids, nanoparticles, proteins, protein-antibody complexes, peptides, cellulose, nanogel, or a combination thereof.

In some embodiments, the composition is formulated to cross the blood brain barrier. In some embodiments, the composition is formulated for central nervous system (CNS) delivery. In some embodiments, the composition includes a lipophilic compound. The lipophilic compound may be useful for crossing the blood brain barrier or for CNS delivery.

In some embodiments, the composition is formulated for administration. The administration may be systemic. In some embodiments, the administration is intravenous. In some embodiments, the administration is by injection. In some embodiments, the injection is subcutaneous. In some embodiments, the injection is subcutaneous. In some embodiments, the injection is intraperitoneal. In some embodiments, the injection is intramuscular. The administration may be to an eye (e.g. intravitreal). The administration may be to a neural tissue. The administration may be to a brain. The administration may be intracerebroventricular. In some embodiments, the formulation allows for delivery of a compound such as an oligonucleotide to a neural cell.

Disclosed herein, in some embodiments, are methods of administering a composition described herein to a subject. Some embodiments relate to use a composition described herein, such as administering the composition to a subject.

Some embodiments relate to a method of treating a disorder in a subject in need thereof. Some embodiments relate to use of a composition described herein in the method of treatment. Some embodiments include administering a composition described herein to a subject with the disorder. In some embodiments, the administration treats the disorder in the subject. In some embodiments, the composition treats the disorder in the subject.

In some embodiments, the treatment comprises prevention, inhibition, or reversion of the disorder in the subject. Some embodiments relate to use of a composition described herein in the method of preventing, inhibiting, or reversing the disorder. Some embodiments relate to a method of preventing, inhibiting, or reversing a disorder a disorder in a subject in need thereof. Some embodiments include administering a composition described herein to a subject with the disorder. In some embodiments, the administration prevents, inhibits, or reverses the disorder in the subject. In some embodiments, the composition prevents, inhibits, or reverses the disorder in the subject.

Some embodiments relate to a method of preventing a disorder a disorder in a subject in need thereof. Some embodiments relate to use of a composition described herein in the method of preventing the disorder. Some embodiments include administering a composition described herein to a subject with the disorder. In some embodiments, the administration prevents the disorder in the subject. In some embodiments, the composition prevents the disorder in the subject.

Some embodiments relate to a method of inhibiting a disorder a disorder in a subject in need thereof. Some embodiments relate to use of a composition described herein in the method of inhibiting the disorder. Some embodiments include administering a composition described herein to a subject with the disorder. In some embodiments, the administration inhibits the disorder in the subject. In some embodiments, the composition inhibits the disorder in the subject.

Some embodiments relate to a method of reversing a disorder a disorder in a subject in need thereof. Some embodiments relate to use of a composition described herein in the method of reversing the disorder. Some embodiments include administering a composition described herein to a subject with the disorder. In some embodiments, the administration reverses the disorder in the subject. In some embodiments, the composition reverses the disorder in the subject.

In some embodiments, the administration is systemic. In some embodiments, the administration is intravenous. In some embodiments, the administration is by injection. In some embodiments, the injection is subcutaneous. In some embodiments, the injection is subcutaneous. In some embodiments, the injection is intraperitoneal. In some embodiments, the injection is intramuscular. The administration may be to an eye (e.g. intravitreal). The administration may be to a neural tissue. The administration may be to a brain. The administration may be intracerebroventricular.

Some embodiments of the methods described herein include treating a disorder in a subject in need thereof. In some embodiments, the disorder is a neurological disorder. Non-limiting examples of neurological disorders include dementia, Alzheimer's disease, delirium, cognitive decline, vascular dementia, or Parkinson's disease. In some embodiments, the neurological disorder includes cognitive decline. In some embodiments, the neurological disorder includes delirium. In some embodiments, the neurological disorder includes dementia. In some embodiments, the neurological disorder includes vascular dementia. In some embodiments, the neurological disorder includes Alzheimer's disease. In some embodiments, the neurological disorder includes Parkinson's disease. The neurological disorder may include a neurodegenerative disease. The neurological disorder may be characterized by protein aggregation.

Some embodiments of the methods described herein include treatment of a subject. Non-limiting examples of subjects include vertebrates, animals, mammals, dogs, cats, cattle, rodents, mice, rats, primates, monkeys, and humans. In some embodiments, the subject is a vertebrate. In some embodiments, the subject is an animal. In some embodiments, the subject is a mammal. In some embodiments, the subject is a dog. In some embodiments, the subject is a cat. In some embodiments, the subject is a cattle. In some embodiments, the subject is a mouse. In some embodiments, the subject is a rat. In some embodiments, the subject is a primate. In some embodiments, the subject is a monkey. In some embodiments, the subject is an animal, a mammal, a dog, a cat, cattle, a rodent, a mouse, a rat, a primate, or a monkey. In some embodiments, the subject is a human.

In some embodiments, the subject is male. In some embodiments, the subject is female.

In some embodiments, the subject is an adult (e.g. at least 18 years old). In some embodiments, the subject is ≥90 years of age. In some embodiments, the subject is ≥85 years of age. In some embodiments, the subject is ≥80 years of age. In some embodiments, the subject is ≥70 years of age. In some embodiments, the subject is ≥60 years of age. In some embodiments, the subject is ≥50 years of age. In some embodiments, the subject is ≥40 years of age. In some embodiments, the subject is ≥30 years of age. In some embodiments, the subject is ≥20 years of age. In some embodiments, the subject is ≥10 years of age. In some embodiments, the subject is ≥1 years of age. In some embodiments, the subject is ≥0 years of age.

In some embodiments, the subject is ≤100 years of age. In some embodiments, the subject is ≤90 years of age. In some embodiments, the subject is ≤85 years of age. In some embodiments, the subject is ≤80 years of age. In some embodiments, the subject is ≤70 years of age. In some embodiments, the subject is ≤60 years of age. In some embodiments, the subject is ≤50 years of age. In some embodiments, the subject is ≤40 years of age. In some embodiments, the subject is ≤30 years of age. In some embodiments, the subject is ≤20 years of age. In some embodiments, the subject is ≤10 years of age. In some embodiments, the subject is ≤1 years of age.

In some embodiments, the subject is between 0 and 100 years of age. In some embodiments, the subject is between 20 and 90 years of age. In some embodiments, the subject is between 30 and 80 years of age. In some embodiments, the subject is between 40 and 75 years of age. In some embodiments, the subject is between 50 and 70 years of age. In some embodiments, the subject is between 40 and 85 years of age.

Disclosed herein, in some embodiments, are systems, methods and kits for detecting one or more genotypes. In some embodiments, the genotypes described herein are detected using suitable genotyping devices (e.g., array, sequencing). In some instances, a sample is obtained from the subject or patient indirectly or directly. In some instances, the sample may be obtained by the subject. In other instances, the sample may be obtained by a healthcare professional, such as a nurse or physician. The sample may be derived from virtually any biological fluid or tissue containing genetic information, such as blood. Methods disclosed herein for detecting a genotype in a sample from a subject comprise analyzing the genetic material in the sample to detect at least one of a presence, an absence, and a quantity of a nucleic acid sequence encompassing the genotype of interest.

In some embodiments, the genotype is a genotype at risk for developing Alzheimer's disease or dementia. In some embodiments, the subject is a heterozygous carrier of APOE4. In some embodiments, the subject is a homozygous carrier of APOE4. In some embodiments, the subject is a heterozygous carrier of MTRES1 rs117058816-G (c.3+1G). In some embodiments, the subject is a homozygous carrier of MTRES1 rs117058816-G (c.3+1G).

In some embodiments, a polygenic risk score is calculated. In some embodiments, the polygenic risk score includes APOE. In some embodiments, the polygenic risk score does not include APOE. In some embodiments, the polygenic risk score includes at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 variants. In some embodiments, the polygenic risk score includes at least about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, 10,000 or more variants. In some embodiments, the polygenic risk score includes at least 1000, 10,000, 100,000, 1,000,000 or more variants.

In some embodiments, the steps of calculating a polygenic risk score comprise providing a sample from a subject, optionally purifying DNA from the sample by processing the sample, assaying the optionally processed sample to detect genotypes of at least two genetic loci in the sample, processing the genotypes to produce a polygenic risk score (PRS), calculating the percentile risk of the subject by comparing the PRS to a reference population and selecting a therapy to treat a disease or disorder of the subject based on the percentile.

th th th th th th th rd nd st th th In some embodiments, a subject is at risk for developing Alzheimer's disease or dementia if the subject has a polygenic risk scope in the upper 50percentile, 40percentile, 30percentile, 20percentile, 10percentile, 5percentile, 4percentile, 3percentile, 2percentile, or 1percentile. In some embodiments, a subject is at risk for developing Alzheimer's disease or dementia if the subject has a polygenic risk score in the upper 20percentile. In some embodiments, a subject is at risk for developing Alzheimer's disease or dementia if the subject has a polygenic risk score in the upper 40percentile.

Nucleic acid-based detection techniques that may be useful for the methods herein include quantitative polymerase chain reaction (qPCR), gel electrophoresis, immunochemistry, in situ hybridization such as fluorescent in situ hybridization (FISH), cytochemistry, and next generation sequencing. In some embodiments, the methods involve TaqMan™ qPCR, which involves a nucleic acid amplification reaction with a specific primer pair, and hybridization of the amplified nucleic acids with a hydrolysable probe specific to a target nucleic acid.

In some instances, the methods involve hybridization and/or amplification assays that include, but are not limited to, Southern or Northern analyses, polymerase chain reaction analyses, and probe arrays. Non-limiting amplification reactions include, but are not limited to, qPCR, self-sustained sequence replication, transcriptional amplification system, Q-Beta Replicase, rolling circle replication, or any other nucleic acid amplification known in the art. As discussed, reference to qPCR herein includes use of TaqMan™ methods. An additional exemplary hybridization assay includes the use of nucleic acid probes conjugated or otherwise immobilized on a bead, multi-well plate, or other substrate, wherein the nucleic acid probes are configured to hybridize with a target nucleic acid sequence of a genotype provided herein. A non-limiting method is one employed in Anal Chem. 2013 Feb. 5; 85(3): 1932-9.

In some embodiments, detecting the presence or absence of a genotype comprises sequencing genetic material from the subject. Sequencing can be performed with any appropriate sequencing technology, including but not limited to single-molecule real-time (SMRT) sequencing, Polony sequencing, sequencing by ligation, reversible terminator sequencing, proton detection sequencing, ion semiconductor sequencing, nanopore sequencing, electronic sequencing, pyrosequencing, Maxam-Gilbert sequencing, chain termination (e.g., Sanger) sequencing, +S sequencing, or sequencing by synthesis. Sequencing methods also include next-generation sequencing, e.g., modern sequencing technologies such as Illumina sequencing (e.g., Solexa), Roche 454 sequencing, Ion torrent sequencing, and SOLID sequencing. In some cases, next-generation sequencing involves high-throughput sequencing methods. Additional sequencing methods available to one of skill in the art may also be employed.

In one aspect, the methods provided herein for determining the presence, absence, and/or quantity of a nucleic acid sequence from a particular genotype comprise an amplification reaction such as qPCR. In an exemplary method, genetic material is obtained from a sample of a subject, e.g., a sample of blood or serum. In certain embodiments where nucleic acids are extracted, the nucleic acids are extracted using any technique that does not interfere with subsequent analysis. In certain embodiments, this technique uses alcohol precipitation using ethanol, methanol, or isopropyl alcohol. In certain embodiments, this technique uses phenol, chloroform, or any combination thereof. In certain embodiments, this technique uses cesium chloride. In certain embodiments, this technique uses sodium, potassium or ammonium acetate or any other salt commonly used to precipitate DNA. In certain embodiments, this technique utilizes a column or resin based nucleic acid purification scheme such as those commonly sold commercially, one non-limiting example would be the GenElute Bacterial Genomic DNA Kit available from Sigma Aldrich. In certain embodiments, after extraction the nucleic acid is stored in water, Tris buffer, or Tris-EDTA buffer before subsequent analysis. In an exemplary embodiment, the nucleic acid material is extracted in water. In some cases, extraction does not comprise nucleic acid purification.

Some embodiments of the methods described herein include obtaining a baseline measurement from a subject. For example, in some embodiments, a baseline measurement is obtained from the subject prior to treating the subject. Non-limiting examples of baseline measurements include a baseline cognitive function measurement, a baseline central nervous system (CNS) amyloid plaque measurement, a baseline CNS tau accumulation measurement, a baseline cerebrospinal fluid (CSF) beta-amyloid 42 measurement, a baseline CSF tau measurement, a baseline CSF phospho-tau measurement, a baseline neurofilament light (NfL) measurement. a baseline CSF alpha-synuclein measurement, a baseline Lewy body measurement, a baseline MTRES1 protein measurement, or a baseline MTRES1 mRNA measurement.

In some embodiments, the baseline measurement is obtained directly from the subject. In some embodiments, the baseline measurement is obtained by observation, for example by observation of the subject or of the subject's tissue. In some embodiments, the baseline measurement is obtained noninvasively using an imaging device.

In some embodiments, the baseline measurement is obtained in a sample from the subject. In some embodiments, the baseline measurement is obtained in one or more histological tissue sections. In some embodiments, the baseline measurement is obtained by performing an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay, on the sample obtained from the subject. In some embodiments, the baseline measurement is obtained by an immunoassay, a colorimetric assay, a fluorescence assay, or a chromatography (e.g. HPLC) assay. In some embodiments, the baseline measurement is obtained by PCR.

In some embodiments, the baseline measurement is a baseline cognitive function measurement. The baseline cognitive function measurement may be obtained directly from the subject. For example, the subject may be administered a test. The test may include a cognitive test such as the Montreal Cognitive Assessment (MoCA), Mini-Mental State Exam (MMSE), or Mini-Cog. The test may include assessment of basic cognitive functions such as memory, language, executive frontal lobe function, apraxia, visuospatial ability, behavior, mood, orientation, or attention. The baseline cognitive function measurement may include a score. The baseline cognitive function measurement may be indicative of mild cognitive impairment, or of severe cognitive impairment. The baseline cognitive function measurement may be indicative of a neurological disorder.

The baseline measurement may include a baseline. In some embodiments, the marker of neurodegeneration measurement. Examples of marker of neurodegeneration may include central nervous system (CNS) amyloid plaques, CNS tau accumulation, cerebrospinal fluid (CSF) beta-amyloid 42, CSF tau, CSF phospho-tau, CSF or plasma neurofilament light chain (NfL), Lewy bodies, or CSF alpha-synuclein. Any of these measurements may be reduced in relation to the baseline measurement. Some examples of ways to measure these may include an assay such as an immunoassay, colorimetric assay, or microscopy.

In some embodiments, the baseline measurement is a baseline amyloid plaque measurement. The baseline amyloid plaque measurement may include a central nervous system (CNS) amyloid plaque measurement. In some embodiments, the baseline amyloid plaque measurement includes a baseline concentration or amount. The baseline amyloid plaque measurement may be performed using an imaging device. The imaging device may include a positron emission tomography (PET) device. The baseline amyloid plaque measurement may be performed on a biopsy. The baseline amyloid plaque measurement may be performed using a spinal tap (for example, when the baseline amyloid plaque measurement includes a baseline cerebrospinal fluid (CSF) amyloid plaque measurement). In some embodiments, the baseline amyloid plaque measurement is obtained by an assay such as an immunoassay. The baseline beta amyloid plaque measurement may be indicative of a neurodegenerative disease such as Alzheimer's disease.

In some embodiments, the baseline measurement is a baseline beta-amyloid 42 measurement. The baseline beta-amyloid 42 measurement may include a cerebrospinal fluid (CSF) beta-amyloid 42 measurement. In some embodiments, the baseline beta-amyloid 42 measurement includes a baseline concentration or amount. The baseline beta-amyloid 42 measurement may be performed on a biopsy. The baseline beta-amyloid 42 measurement may be performed using a spinal tap (for example, when the baseline beta-amyloid 42 measurement includes a baseline CSF beta-amyloid 42 measurement). In some embodiments, the baseline beta-amyloid 42 measurement is obtained by an assay such as an immunoassay. The baseline beta-amyloid 42 measurement may be indicative of a neurodegenerative disease such as Alzheimer's disease.

In some embodiments, the baseline measurement is a baseline tau measurement. In some embodiments, the baseline tau measurement includes a baseline concentration or amount. The baseline tau measurement may be performed on a biopsy. In some embodiments, the baseline tau measurement is obtained by an assay such as an immunoassay. The baseline beta tau measurement may be indicative of a neurodegenerative disease such as Alzheimer's disease or Parkinson's disease.

In some embodiments, the baseline tau measurement is a baseline central nervous system (CNS) tau measurement. The baseline tau measurement may include a baseline total tau measurement. The baseline tau measurement may include a baseline unphosphorylated tau measurement. The baseline tau measurement may include a baseline phosphorylated tau (phospho-tau) measurement. In some embodiments, the baseline tau measurement is a baseline tau accumulation measurement. In some embodiments, the baseline tau measurement is a baseline CNS tau accumulation measurement. The baseline CNS tau accumulation measurement may be indicative of a neurodegenerative disease such as Alzheimer's disease or Parkinson's disease.

The baseline tau measurement may include a cerebrospinal fluid (CSF) tau measurement. The baseline CSF tau measurement may be performed after use of a spinal tap. The baseline CSF tau measurement may be indicative of a neurodegenerative disease such as Alzheimer's disease or Parkinson's disease.

The baseline CSF tau measurement may include a baseline CSF phospho-tau measurement. The baseline CSF phospho-tau measurement may include an amount of phospho-tau in relation to total tau or unphosphorylated tau. For example, the baseline CSF phospho-tau measurement may include a phospho-tau/tau ratio. The baseline CSF phospho-tau measurement may be indicative of a neurodegenerative disease such as Alzheimer's disease or Parkinson's disease.

In some embodiments, the baseline neurofilament light chain (NfL) measurement includes a baseline CSF or plasma NfL measurement. The baseline NfL measurement may be a baseline CSF NfL measurement. The baseline NfL measurement may be a baseline plasma NfL measurement. The NfL measurement may include a concentration or an amount. The baseline NfL measurement may be indicative of a neurodegenerative disease such as Alzheimer's disease or Parkinson's disease.

In some embodiments, the baseline measurement is a baseline alpha-synuclein measurement. The baseline alpha-synuclein measurement may include a cerebrospinal fluid (CSF) alpha-synuclein measurement. In some embodiments, the baseline alpha-synuclein measurement includes a baseline concentration or amount. The baseline alpha-synuclein measurement may be performed on a biopsy. The baseline alpha-synuclein measurement may be performed using a spinal tap (for example, when the baseline alpha-synuclein measurement includes a baseline CSF alpha-synuclein measurement). In some embodiments, the baseline alpha-synuclein measurement is obtained by an assay such as an immunoassay. The baseline alpha-synuclein measurement may be indicative of a neurodegenerative disease such as Parkinson's disease. The baseline alpha-synuclein measurement may be indicative of dementia.

In some embodiments, the baseline measurement is a baseline Lewy body measurement. The baseline Lewy body measurement may include a central nervous system (CNS) Lewy body measurement. In some embodiments, the baseline Lewy body measurement includes a baseline concentration or amount. The baseline Lewy body measurement may be performed using an imaging device. The imaging device may include a positron emission tomography (PET) device. The baseline beta Lewy body measurement may be indicative of dementia.

In some embodiments, the baseline measurement is a baseline MTRES1 protein measurement. In some embodiments, the baseline MTRES1 protein measurement comprises a baseline MTRES1 protein level. In some embodiments, the baseline MTRES1 protein level is indicated as a mass or percentage of MTRES1 protein per sample weight. In some embodiments, the baseline MTRES1 protein level is indicated as a mass or percentage of MTRES1 protein per sample volume. In some embodiments, the baseline MTRES1 protein level is indicated as a mass or percentage of MTRES1 protein per total protein within the sample. In some embodiments, the baseline MTRES1 protein measurement is a baseline CNS or CSF MTRES1 protein measurement. In some embodiments, the baseline MTRES1 protein measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay.

In some embodiments, the baseline measurement is a baseline MTRES1 mRNA measurement. In some embodiments, the baseline MTRES1 mRNA measurement comprises a baseline MTRES1 mRNA level. In some embodiments, the baseline MTRES1 mRNA level is indicated as an amount or percentage of MTRES1 mRNA per sample weight. In some embodiments, the baseline MTRES1 mRNA level is indicated as an amount or percentage of MTRES1 mRNA per sample volume. In some embodiments, the baseline MTRES1 mRNA level is indicated as an amount or percentage of MTRES1 mRNA per total mRNA within the sample. In some embodiments, the baseline MTRES1 mRNA level is indicated as an amount or percentage of MTRES1 mRNA per total nucleic acids within the sample. In some embodiments, the baseline MTRES1 mRNA level is indicated relative to another mRNA level, such as an mRNA level of a housekeeping gene, within the sample. In some embodiments, the baseline MTRES1 mRNA measurement is a baseline CNS or CSF MTRES1 mRNA measurement. In some embodiments, the baseline MTRES1 mRNA measurement is obtained by an assay such as a polymerase chain reaction (PCR) assay. In some embodiments, the PCR comprises quantitative PCR (qPCR). In some embodiments, the PCR comprises reverse transcription of the MTRES1 mRNA.

Some embodiments of the methods described herein include obtaining a sample from a subject. In some embodiments, the baseline measurement is obtained in a sample obtained from the subject. In some embodiments, the sample is obtained from the subject prior to administration or treatment of the subject with a composition described herein. In some embodiments, a baseline measurement is obtained in a sample obtained from the subject prior to administering the composition to the subject.

In some embodiments, the sample comprises a fluid. In some embodiments, the sample is a fluid sample. In some embodiments, the fluid sample is a CSF sample. In some embodiments, the fluid sample includes a central nervous system (CNS) fluid sample. The CNS fluid may include cerebrospinal fluid (CSF). In some embodiments, the fluid sample includes a CSF sample. In In some embodiments, the sample is a blood, plasma, or serum sample. In some embodiments, the sample comprises blood. In some embodiments, the sample is a blood sample. In some embodiments, the sample is a whole-blood sample. In some embodiments, the blood is fractionated or centrifuged. In some embodiments, the sample comprises plasma. In some embodiments, the sample is a plasma sample. A blood sample may be a plasma sample. In some embodiments, the sample comprises serum. In some embodiments, the sample is a serum sample. A blood sample may be a serum sample.

In some embodiments, the sample comprises a tissue. In some embodiments, the sample is a tissue sample. In some embodiments, the tissue comprises central nervous system (CNS) tissue. For example, the baseline MTRES1 mRNA measurement, or the baseline MTRES1 protein measurement, may be obtained in a CNS tissue sample obtained from the patient. The CNS tissue may include brain tissue. The CNS tissue may include nerve tissue. The CNS tissue may include neurons, glia, microglia, astrocytes, or oligodendrocytes, or a combination thereof. The CNS tissue may include neurons. The CNS tissue may include glia. The CNS tissue may include microglia. The CNS tissue may include astrocytes. The CNS tissue may include oligodendrocytes.

In some embodiments, the sample includes cells. In some embodiments, the sample comprises a cell. In some embodiments, the cell comprises a CNS cell. The CNS cell may include a brain cell. The CNS cell may include a nerve cell. The CNS cell may be a neuron, glial cell, microglial cell, astrocyte, or oligodendrocyte. The CNS cell may be a neuron. The CNS cell may be a glial cell. The CNS cell may be a microglial cell. The CNS cell may be an astrocyte. The CNS cell may be an oligodendrocyte.

In some embodiments, the composition or administration of the composition affects a measurement such as a cognitive function measurement, a central nervous system (CNS) amyloid plaque measurement, a CNS tau accumulation measurement, a cerebrospinal fluid (CSF) beta-amyloid 42 measurement, a CSF tau measurement, a CSF phospho-tau measurement, a NfL measurement, a CSF alpha-synuclein measurement, a Lewy body measurement, a MTRES1 protein measurement, or a MTRES1 mRNA measurement, relative to the baseline measurement.

Some embodiments of the methods described herein include obtaining the measurement from a subject. For example, the measurement may be obtained from the subject after treating the subject. In some embodiments, the measurement is obtained in a second sample (such as a fluid or tissue sample described herein) obtained from the subject after the composition is administered to the subject. In some embodiments, the measurement is an indication that the disorder has been treated.

In some embodiments, the measurement is obtained directly from the subject. In some embodiments, the measurement is obtained noninvasively using an imaging device. In some embodiments, the measurement is obtained in a second sample from the subject. In some embodiments, the measurement is obtained in one or more histological tissue sections. In some embodiments, the measurement is obtained by performing an assay on the second sample obtained from the subject. In some embodiments, the measurement is obtained by an assay, such as an assay described herein. In some embodiments, the assay is an immunoassay, a colorimetric assay, a fluorescence assay, a chromatography (e.g. HPLC) assay, or a PCR assay. In some embodiments, the measurement is obtained by an assay such as an immunoassay, a colorimetric assay, a fluorescence assay, or a chromatography (e.g. HPLC) assay. In some embodiments, the measurement is obtained by PCR. In some embodiments, the measurement is obtained by histology. In some embodiments, the measurement is obtained by observation. In some embodiments, additional measurements are made, such as in a third sample, a fourth sample, or a fifth sample.

In some embodiments, the measurement is obtained within 1 hour, within 2 hours, within 3 hours, within 4 hours, within 5 hours, within 6 hours, within 12 hours, within 18 hours, or within 24 hours after the administration of the composition. In some embodiments, the measurement is obtained within 1 day, within 2 days, within 3 days, within 4 days, within 5 days, within 6 days, or within 7 days after the administration of the composition. In some embodiments, the measurement is obtained within 1 week, within 2 weeks, within 3 weeks, within 1 month, within 2 months, within 3 months, within 6 months, within 1 year, within 2 years, within 3 years, within 4 years, or within 5 years after the administration of the composition. In some embodiments, the measurement is obtained after 1 hour, after 2 hours, after 3 hours, after 4 hours, after 5 hours, after 6 hours, after 12 hours, after 18 hours, or after 24 hours after the administration of the composition. In some embodiments, the measurement is obtained after 1 day, after 2 days, after 3 days, after 4 days, after 5 days, after 6 days, or after 7 days after the administration of the composition. In some embodiments, the measurement is obtained after 1 week, after 2 weeks, after 3 weeks, after 1 month, after 2 months, after 3 months, after 6 months, after 1 year, after 2 years, after 3 years, after 4 years, or after 5 years, following the administration of the composition.

In some embodiments, the composition reduces the measurement relative to the baseline measurement. For example, an adverse phenotype of a neurological disorder may be reduced upon administration of the composition. The neurological disorder may include dementia, Alzheimer's disease, delirium, cognitive decline, vascular dementia, or Parkinson's disease. In some embodiments, the reduction is measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the reduction is measured directly in the subject after administering the composition to the subject. In some embodiments, the measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline measurement. In some embodiments, the measurement is decreased by about 10% or more, relative to the baseline measurement. In some embodiments, the measurement is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline measurement. In some embodiments, the measurement is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline measurement. In some embodiments, the measurement is decreased by no more than about 10%, relative to the baseline measurement. In some embodiments, the measurement is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline measurement. In some embodiments, the measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.

In some embodiments, the composition increases the measurement relative to the baseline measurement. For example, a protective phenotype of a neurological disorder may be increased upon administration of the composition. The neurological disorder may include dementia, Alzheimer's disease, delirium, cognitive decline, vascular dementia, or Parkinson's disease. In some embodiments, the increase is measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the increase is measured directly in the subject after administering the composition to the subject. In some embodiments, the measurement is increased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline measurement. In some embodiments, the measurement is increased by about 10% or more, relative to the baseline measurement. In some embodiments, the measurement is increased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline measurement. In some embodiments, the measurement is increased by about 100% or more, increased by about 250% or more, increased by about 500% or more, increased by about 750% or more, or increased by about 1000% or more, relative to the baseline measurement. In some embodiments, the measurement is increased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline measurement. In some embodiments, the measurement is increased by no more than about 10%, relative to the baseline measurement. In some embodiments, the measurement is increased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline measurement. In some embodiments, the measurement is increased by no more than about 100%, increased by no more than about 250%, increased by no more than about 500%, increased by no more than about 750%, or increased by no more than about 1000%, relative to the baseline measurement. In some embodiments, the measurement is increased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 250%, 500%, 750%, or 1000%, or by a range defined by any of the two aforementioned percentages.

In some embodiments, the measurement is a cognitive function measurement. The cognitive function measurement may be obtained directly from the subject. For example, the subject may be administered a test. The test may include a cognitive test such as the Montreal Cognitive Assessment (MoCA), Mini-Mental State Exam (MMSE), or Mini-Cog. The test may include assessment of basic cognitive functions such as memory, language, executive frontal lobe function, apraxia, visuospatial ability, behavior, mood, orientation, or attention. The cognitive function measurement may include a score. The cognitive function measurement may be indicative of a lack of cognitive impairment. In some embodiments, the cognitive function measurement is indicative of mild cognitive impairment, and the baseline cognitive function measurement is indicative of severe cognitive impairment. The cognitive function measurement may be indicative of a neurological disorder.

In some embodiments, the composition increases the cognitive function measurement relative to the baseline cognitive function measurement. In some embodiments, the increase is measured directly in the subject after administering the composition to the subject. In some embodiments, the cognitive function measurement is increased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline cognitive function measurement. In some embodiments, the cognitive function measurement is increased by about 10% or more, relative to the baseline cognitive function measurement. In some embodiments, the cognitive function measurement is increased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline cognitive function measurement. In some embodiments, the cognitive function measurement is increased by about 100% or more, increased by about 250% or more, increased by about 500% or more, increased by about 750% or more, or increased by about 1000% or more, relative to the baseline cognitive function measurement. In some embodiments, the cognitive function measurement is increased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline cognitive function measurement. In some embodiments, the cognitive function measurement is increased by no more than about 10%, relative to the baseline cognitive function measurement. In some embodiments, the cognitive function measurement is increased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline cognitive function measurement. In some embodiments, the cognitive function measurement is increased by no more than about 100%, increased by no more than about 250%, increased by no more than about 500%, increased by no more than about 750%, or increased by no more than about 1000%, relative to the baseline cognitive function measurement. In some embodiments, the cognitive function measurement is increased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 250%, 500%, 750%, or 1000%, or by a range defined by any of the two aforementioned percentages.

In some embodiments, the measurement is an amyloid plaque measurement. The amyloid plaque measurement may include a central nervous system (CNS) amyloid plaque measurement. In some embodiments, the amyloid plaque measurement includes a concentration or amount. The amyloid plaque measurement may be performed using an imaging device. The imaging device may include a positron emission tomography (PET) device. The amyloid plaque measurement may be performed on a biopsy. The amyloid plaque measurement may be performed using a spinal tap (for example, when the amyloid plaque measurement includes a cerebrospinal fluid (CSF) amyloid plaque measurement). In some embodiments, the amyloid plaque measurement is obtained by an assay such as an immunoassay. The beta amyloid plaque measurement may be indicative of a treatment effect of the oligonucleotide on a neurodegenerative disease such as Alzheimer's disease.

In some embodiments, the composition reduces the amyloid plaque measurement relative to the baseline amyloid plaque measurement. In some embodiments, the reduction is measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the reduction is measured directly in the subject after administering the composition to the subject. In some embodiments, the amyloid plaque measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline amyloid plaque measurement. In some embodiments, the amyloid plaque measurement is decreased by about 10% or more, relative to the baseline amyloid plaque measurement. In some embodiments, the amyloid plaque measurement is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline amyloid plaque measurement. In some embodiments, the amyloid plaque measurement is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline amyloid plaque measurement. In some embodiments, the amyloid plaque measurement is decreased by no more than about 10%, relative to the baseline amyloid plaque measurement. In some embodiments, the amyloid plaque measurement is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline amyloid plaque measurement. In some embodiments, the amyloid plaque measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.

In some embodiments, the measurement is a beta-amyloid 42 measurement. The beta-amyloid 42 measurement may include a cerebrospinal fluid (CSF) beta-amyloid 42 measurement. In some embodiments, the beta-amyloid 42 measurement includes a concentration or amount. The beta-amyloid 42 measurement may be performed on a biopsy. The beta-amyloid 42 measurement may be performed using a spinal tap (for example, when the beta-amyloid 42 measurement includes a CSF beta-amyloid 42 measurement). In some embodiments, the beta-amyloid 42 measurement is obtained by an assay such as an immunoassay. The beta-amyloid 42 measurement may be indicative of a treatment effect of the oligonucleotide on a neurodegenerative disease such as Alzheimer's disease.

In some embodiments, the composition reduces the CSF beta-amyloid 42 measurement relative to the baseline beta-amyloid 42 measurement. In some embodiments, the reduction is measured in a second sample (for example, a CSF sample) obtained from the subject after administering the composition to the subject. In some embodiments, the CSF beta-amyloid 42 measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline CSF beta-amyloid 42 measurement. In some embodiments, the CSF beta-amyloid 42 measurement is decreased by about 10% or more, relative to the baseline CSF beta-amyloid 42 measurement. In some embodiments, the CSF beta-amyloid 42 measurement is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline CSF beta-amyloid 42 measurement. In some embodiments, the CSF beta-amyloid 42 measurement is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline CSF beta-amyloid 42 measurement. In some embodiments, the CSF beta-amyloid 42 measurement is decreased by no more than about 10%, relative to the baseline CSF beta-amyloid 42 measurement. In some embodiments, the CSF beta-amyloid 42 measurement is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline CSF beta-amyloid 42 measurement. In some embodiments, the CSF beta-amyloid 42 measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.

In some embodiments, the measurement is a tau measurement. In some embodiments, the tau measurement includes a concentration or amount. The tau measurement may be performed on a biopsy. In some embodiments, the tau measurement is obtained by an assay such as an immunoassay. The beta tau measurement may be indicative of a treatment effect of the oligonucleotide on a neurodegenerative disease such as Alzheimer's disease or Parkinson's disease.

In some embodiments, the tau measurement is a central nervous system (CNS) tau measurement. The tau measurement may include a total tau measurement. The tau measurement may include a unphosphorylated tau measurement. The tau measurement may include a phosphorylated tau (phospho-tau) measurement. In some embodiments, the tau measurement is a tau accumulation measurement. In some embodiments, the tau measurement is a CNS tau accumulation measurement. The CNS tau accumulation measurement may be indicative of a treatment effect of the oligonucleotide on a neurodegenerative disease such as Alzheimer's disease or Parkinson's disease.

In some embodiments, the composition reduces the CNS tau accumulation measurement relative to the baseline CNS tau accumulation measurement. In some embodiments, the reduction is measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the CNS tau accumulation measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline CNS tau accumulation measurement. In some embodiments, the CNS tau accumulation measurement is decreased by about 10% or more, relative to the baseline CNS tau accumulation measurement. In some embodiments, the CNS tau accumulation measurement is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline CNS tau accumulation measurement. In some embodiments, the CNS tau accumulation measurement is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline CNS tau accumulation measurement. In some embodiments, the CNS tau accumulation measurement is decreased by no more than about 10%, relative to the baseline CNS tau accumulation measurement. In some embodiments, the CNS tau accumulation measurement is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline CNS tau accumulation measurement. In some embodiments, the CNS tau accumulation measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.

The tau measurement may include a cerebrospinal fluid (CSF) tau measurement. The CSF tau measurement may be performed after use of a spinal tap. The CSF tau measurement may be indicative of a treatment effect of the oligonucleotide on a neurodegenerative disease such as Alzheimer's disease or Parkinson's disease.

In some embodiments, the composition reduces the CSF tau measurement relative to the baseline CSF tau measurement. In some embodiments, the reduction is measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the reduction is measured in a second CSF sample obtained from the subject after administering the composition to the subject. In some embodiments, the CSF tau measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline CSF tau measurement. In some embodiments, the CSF tau measurement is decreased by about 10% or more, relative to the baseline CSF tau measurement. In some embodiments, the CSF tau measurement is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline CSF tau measurement. In some embodiments, the CSF tau measurement is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline CSF tau measurement. In some embodiments, the CSF tau measurement is decreased by no more than about 10%, relative to the baseline CSF tau measurement. In some embodiments, the CSF tau measurement is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline CSF tau measurement. In some embodiments, the CSF tau measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.

The CSF tau measurement may include a CSF phospho-tau measurement. The CSF phospho-tau measurement may include an amount of phospho-tau in relation to total tau or unphosphorylated tau. For example, the CSF phospho-tau measurement may include a phospho-tau/tau ratio. The CSF phospho-tau measurement may be indicative of a treatment effect of the oligonucleotide on a neurodegenerative disease such as Alzheimer's disease or Parkinson's disease.

In some embodiments, the composition reduces the CSF phospho-tau measurement relative to the baseline CSF phospho-tau measurement. In some embodiments, the reduction is measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the reduction is measured in a second CSF sample obtained from the subject after administering the composition to the subject. In some embodiments, the CSF phospho-tau measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline CSF phospho-tau measurement. In some embodiments, the CSF phospho-tau measurement is decreased by about 10% or more, relative to the baseline CSF phospho-tau measurement. In some embodiments, the CSF phospho-tau measurement is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline CSF phospho-tau measurement. In some embodiments, the CSF phospho-tau measurement is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline CSF phospho-tau measurement. In some embodiments, the CSF phospho-tau measurement is decreased by no more than about 10%, relative to the baseline CSF phospho-tau measurement. In some embodiments, the CSF phospho-tau measurement is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline CSF phospho-tau measurement. In some embodiments, the CSF phospho-tau measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.

In some embodiments, the neurofilament light chain (NfL) measurement includes a CSF or plasma NfL measurement. The NfL measurement may be a CSF NfL measurement. The NfL measurement may be a plasma NfL measurement. The NfL measurement may include a concentration or an amount. The NfL measurement may be indicative of a neurodegenerative disease such as Alzheimer's disease or Parkinson's disease.

In some embodiments, the composition reduces the NfL measurement relative to the baseline NfL measurement. In some embodiments, the reduction is measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the NfL measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline NfL measurement. In some embodiments, the NfL measurement is decreased by about 10% or more, relative to the baseline NfL measurement. In some embodiments, the NfL measurement is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline NfL measurement. In some embodiments, the NfL measurement is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline NfL measurement. In some embodiments, the NfL measurement is decreased by no more than about 10%, relative to the baseline NfL measurement. In some embodiments, the NfL measurement is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline NfL measurement. In some embodiments, the NfL measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.

In some embodiments, the measurement is an alpha-synuclein measurement. The alpha-synuclein measurement may include a cerebrospinal fluid (CSF) alpha-synuclein measurement. In some embodiments, the alpha-synuclein measurement includes a concentration or amount. The alpha-synuclein measurement may be performed on a biopsy. The alpha-synuclein measurement may be performed using a spinal tap (for example, when the alpha-synuclein measurement includes a CSF alpha-synuclein measurement). In some embodiments, the alpha-synuclein measurement is obtained by an assay such as an immunoassay. The alpha-synuclein measurement may be indicative of a treatment effect of the oligonucleotide on a neurodegenerative disease such as Parkinson's disease. The alpha-synuclein measurement may be indicative of a treatment effect of the oligonucleotide on dementia.

In some embodiments, the composition reduces the alpha-synuclein measurement relative to the baseline alpha-synuclein measurement. In some embodiments, the reduction is measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the alpha-synuclein measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline alpha-synuclein measurement. In some embodiments, the alpha-synuclein measurement is decreased by about 10% or more, relative to the baseline alpha-synuclein measurement. In some embodiments, the alpha-synuclein measurement is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline alpha-synuclein measurement. In some embodiments, the alpha-synuclein measurement is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline alpha-synuclein measurement. In some embodiments, the alpha-synuclein measurement is decreased by no more than about 10%, relative to the baseline alpha-synuclein measurement. In some embodiments, the alpha-synuclein measurement is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline alpha-synuclein measurement. In some embodiments, the alpha-synuclein measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.

In some embodiments, the measurement is a Lewy body measurement. The Lewy body measurement may include a central nervous system (CNS) Lewy body measurement. In some embodiments, the Lewy body measurement includes a concentration or amount. The Lewy body measurement may be performed using an imaging device. The imaging device may include a positron emission tomography (PET) device. The beta Lewy body measurement may be indicative of a treatment effect of the oligonucleotide on dementia.

In some embodiments, the composition reduces the Lewy body measurement relative to the baseline Lewy body measurement. In some embodiments, the reduction is measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the reduction is measured directly in the subject after administering the composition to the subject. In some embodiments, the Lewy body measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline Lewy body measurement. In some embodiments, the Lewy body measurement is decreased by about 10% or more, relative to the baseline Lewy body measurement. In some embodiments, the Lewy body measurement is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline Lewy body measurement. In some embodiments, the Lewy body measurement is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline Lewy body measurement. In some embodiments, the Lewy body measurement is decreased by no more than about 10%, relative to the baseline Lewy body measurement. In some embodiments, the Lewy body measurement is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline Lewy body measurement. In some embodiments, the Lewy body measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.

In some embodiments, the measurement is an MTRES1 protein measurement. In some embodiments, the MTRES1 protein measurement comprises an MTRES1 protein level. In some embodiments, the MTRES1 protein level is indicated as a mass or percentage of MTRES1 protein per sample weight. In some embodiments, the MTRES1 protein level is indicated as a mass or percentage of MTRES1 protein per sample volume. In some embodiments, the MTRES1 protein level is indicated as a mass or percentage of MTRES1 protein per total protein within the sample. In some embodiments, the MTRES1 protein measurement is a CNS tissue or fluid MTRES1 protein measurement. In some embodiments, the MTRES1 protein measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay.

In some embodiments, the composition reduces the MTRES1 protein measurement relative to the baseline MTRES1 protein measurement. In some embodiments, the composition reduces CNS tissue or fluid MTRES1 protein levels relative to the baseline MTRES1 protein measurement. In some embodiments, the reduced MTRES1 protein levels are measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the MTRES1 protein measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline MTRES1 protein measurement. In some embodiments, the MTRES1 protein measurement is decreased by about 10% or more, relative to the baseline MTRES1 protein measurement. In some embodiments, the MTRES1 protein measurement is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, relative to the baseline MTRES1 protein measurement. In some embodiments, the MTRES1 protein measurement is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline MTRES1 protein measurement. In some embodiments, the MTRES1 protein measurement is decreased by no more than about 10%, relative to the baseline MTRES1 protein measurement. In some embodiments, the MTRES1 protein measurement is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline MTRES1 protein measurement. In some embodiments, the MTRES1 protein measurement is decreased by 2.5%, 5%, 7.5%, 19%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.

In some embodiments, the measurement is an MTRES1 mRNA measurement. In some embodiments, the MTRES1 mRNA measurement comprises an MTRES1 mRNA level. In some embodiments, the MTRES1 mRNA level is indicated as an amount or percentage of MTRES1 mRNA per sample weight. In some embodiments, the MTRES1 mRNA level is indicated as an amount or percentage of MTRES1 mRNA per sample volume. In some embodiments, the MTRES1 mRNA level is indicated as an amount or percentage of MTRES1 mRNA per total mRNA within the sample. In some embodiments, the MTRES1 mRNA level is indicated as an amount or percentage of MTRES1 mRNA per total nucleic acids within the sample. In some embodiments, the MTRES1 mRNA level is indicated relative to another mRNA level, such as an mRNA level of a housekeeping gene, within the sample. In some embodiments, the MTRES1 mRNA measurement is a CNS tissue or fluid MTRES1 mRNA measurement. In some embodiments, the MTRES1 mRNA measurement is obtained by an assay such as a PCR assay. In some embodiments, the PCR comprises qPCR. In some embodiments, the PCR comprises reverse transcription of the MTRES1 mRNA.

In some embodiments, the composition reduces the MTRES1 mRNA measurement relative to the baseline MTRES1 mRNA measurement. In some embodiments, the MTRES1 mRNA measurement is obtained in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the composition reduces MTRES1 mRNA levels relative to the baseline MTRES1 mRNA levels. In some embodiments, the reduced MTRES1 mRNA levels are measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the second sample is a CNS sample. In some embodiments, the MTRES1 mRNA measurement is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline MTRES1 mRNA measurement. In some embodiments, the MTRES1 mRNA measurement is decreased by about 10% or more, relative to the baseline MTRES1 mRNA measurement. In some embodiments, the MTRES1 mRNA measurement is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, relative to the baseline MTRES1 mRNA measurement. In some embodiments, the MTRES1 mRNA measurement is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline MTRES1 mRNA measurement. In some embodiments, the MTRES1 mRNA measurement is decreased by no more than about 10%, relative to the baseline MTRES1 mRNA measurement. In some embodiments, the MTRES1 mRNA measurement is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, relative to the baseline MTRES1 mRNA measurement. In some embodiments, the MTRES1 mRNA measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% or by a range defined by any of the two aforementioned percentages.

1. A composition comprising an oligonucleotide that targets MTRES1 and when administered to a subject in an effective amount decreases central nervous system (CNS) MTRES1. 2. The composition of embodiment 1, wherein the CNS MTRES1 decreased by about 10% or more, as compared to prior to administration. 3. A composition comprising an oligonucleotide that targets MTRES1 and when administered to a subject in an effective amount increases cognitive function or slows cognitive decline. 4. The composition of embodiment 3, wherein the cognitive function is increased by about 10% or more, as compared to prior to administration. 5. The composition of embodiment 3, wherein the cognitive decline is slowed by about 10% or more, as compared to prior to administration. 6. A composition comprising an oligonucleotide that targets MTRES1 and when administered to a subject in an effective amount decreases a marker of neurodegeneration. 7. The composition of embodiment 6, wherein the marker of neurodegeneration comprises a central nervous system (CNS) or cerebrospinal fluid (CSF) marker of neurodegeneration. 8. The composition of embodiment 6, wherein the marker of neurodegeneration comprises a measurement of central nervous system (CNS) amyloid plaques, CNS tau accumulation, cerebrospinal fluid (CSF) beta-amyloid 42, CSF tau, CSF phospho-tau, CSF or plasma neurofilament light chain (NfL), Lewy bodies, or CSF alpha-synuclein. 9. The composition of any one of embodiments 6-8, wherein the marker of neurodegeneration is decreased by about 10% or more, as compared to prior to administration. 10. The composition of any one of embodiments 1, 3, or 6, wherein the oligonucleotide comprises a modified internucleoside linkage. 11. The composition of embodiment 10, wherein the modified internucleoside linkage comprises alkylphosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester, or a combination thereof. 12. The composition of embodiment 10, wherein the modified internucleoside linkage comprises one or more phosphorothioate linkages. 13. The composition of any one of embodiments 1, 3, or 6, wherein the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 modified internucleoside linkages. 14. The composition of any one of embodiments 1, 3, or 6, wherein the oligonucleotide comprises a modified nucleoside. 15. The composition of embodiment 14, wherein the modified nucleoside comprises a locked nucleic acid (LNA), hexitol nucleic acid (HNA), cyclohexene nucleic acid (CeNA), 2′-O-methoxyethyl, 2′-O-alkyl, 2′-O-allyl, 2′-O-allyl, 2′-fluoro, or 2′-deoxy, or a combination thereof. 16. The composition of embodiment 14, wherein the modified nucleoside comprises an LNA. 17. The composition of embodiment 14, wherein the modified nucleoside comprises a 2′,4′ constrained ethyl nucleic acid. 18. The composition of embodiment 14, wherein the modified nucleoside comprises a 2′-O-methyl nucleoside, 2′-deoxyfluoro nucleoside, 2′-O—N-methylacetamido (2′-O-NMA) nucleoside, a 2′-O-dimethylaminoethoxyethyl(2′-O-DMAEOE) nucleoside, 2′-O-aminopropyl(2′-O-AP) nucleoside, or 2′-ara-F, or a combination thereof. 19. The composition of embodiment 14, wherein the modified nucleoside comprises one or more 2′fluoro modified nucleosides. 20. The composition of embodiment 14, wherein the modified nucleoside comprises a 2′-O-alkyl modified nucleoside. 21. The composition of any one of embodiments 1, 3, or 6, wherein the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 modified nucleosides. 22. The composition of embodiment any one of embodiments 1, 3, or 6, wherein the oligonucleotide comprises a lipophilic moiety attached at a 3′ or 5′ terminus of the oligonucleotide. 23. The composition of embodiment 22, wherein the lipophilic moiety comprises cholesterol, retinoic acid, cholic acid, adamantane acetic acid, 1-pyrene butyric acid, dihydrotestosterone, 1,3-bis-O(hexadecyl)glycerol, geranyloxyhexyanol, hexadecylglycerol, borneol, menthol, 1,3-propanediol, heptadecyl, palmitic acid, myristic acid, O3-(oleoyl) lithocholic acid, O3-(oleoyl) cholenic acid, ibuprofen, naproxen, dimethoxytrityl, or phenoxazine. 30 24. The composition of embodiment 22, wherein the lipophilic moiety comprises a C4-Chydrocarbon chain. 25. The composition of embodiment 22, wherein the lipophilic moiety comprises a lipid. 26. The composition of embodiment 25, wherein the lipid comprises myristoyl, palmitoyl, stearoyl, lithocholoyl, docosanoyl, docosahexaenoyl, myristyl, palmityl stearyl, or α-tocopherol, or a combination thereof. 27. The composition of embodiment any one of embodiments 1, 3, or 6, wherein the oligonucleotide comprises a small interfering RNA (siRNA) comprising a sense strand and an antisense strand. 28. The composition of embodiment 27, wherein the sense strand is 12-30 nucleosides in length. 29. The composition of embodiment 27, wherein the antisense strand is 12-30 nucleosides in length. 30. A composition comprising an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, each strand is independently about 12-30 nucleosides in length, and at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising about 12-30 contiguous nucleosides of SEQ ID NO: 2443. all purines comprise 2′-fluoro modified purines, and all pyrimidines comprise a mixture of 2′-fluoro and 2′-methyl modified pyrimidines; all purines comprise 2′-methyl modified purines, and all pyrimidines comprise a mixture of 2′-fluoro and 2′-methyl modified pyrimidines; all purines comprise 2′-fluoro modified purines, and all pyrimidines comprise 2′-methyl modified pyrimidines; all pyrimidines comprise 2′-fluoro modified pyrimidines, and all purines comprise a mixture of 2′-fluoro and 2′-methyl modified purines; all pyrimidines comprise 2′-methyl modified pyrimidines, and all purines comprise a mixture of 2′-fluoro and 2′-methyl modified purines; or all pyrimidines comprise 2′-fluoro modified pyrimidines, and all purines comprise 2′-methyl modified purines. 31. The composition of embodiment 27, wherein any one of the following is true with regard to the sense strand: all purines comprise 2′-fluoro modified purines, and all pyrimidines comprise a mixture of 2′-fluoro and 2′-methyl modified pyrimidines; all purines comprise 2′-methyl modified purines, and all pyrimidines comprise a mixture of 2′-fluoro and 2′-methyl modified pyrimidines; all purines comprise 2′-methyl modified purines, and all pyrimidines comprise 2′-fluoro modified pyrimidines; all pyrimidines comprise 2′-fluoro modified pyrimidines, and all purines comprise a mixture of 2′-fluoro and 2′-methyl modified purines; all pyrimidines comprise 2′-methyl modified pyrimidines, and all purines comprise a mixture of 2′-fluoro and 2′-methyl modified purines; or all pyrimidines comprise 2′-methyl modified pyrimidines, and all purines comprise 2′-fluoro modified purines. 32. The composition of embodiment 27, wherein any one of the following is true with regard to the antisense strand: 33. The composition of embodiment 27, wherein the oligonucleotide comprises a phosphate at the 5′ end of the antisense strand. 34. The composition of embodiment 27, wherein the oligonucleotide comprises a phosphate mimic at the 5′ end of the antisense strand. 35. The composition of embodiment 34, wherein the phosphate mimic comprises a 5′-vinyl phosphonate (VP). 36. The composition of any one of embodiments 1, 3, or 6, wherein the oligonucleotide comprises an antisense oligonucleotide (ASO). 37. The composition of embodiment 36, wherein the ASO is 12-30 nucleosides in length. 38. A composition comprising an oligonucleotide that inhibits the expression of MTRES1, wherein the oligonucleotide comprises an ASO about 12-30 nucleosides in length and a nucleoside sequence complementary to about 12-30 contiguous nucleosides of SEQ ID NO: 2443. 39. The composition of any one of embodiments 1, 3, 6, or 38, further comprising a pharmaceutically acceptable carrier. 40. A method of treating a subject having a neurological disorder, comprising administering an effective amount of the composition of embodiment 39 to the subject. 41. The method of embodiment 40, wherein the neurological disorder comprises dementia, Alzheimer's disease, delirium, cognitive decline, vascular dementia, or Parkinson's disease. Also described herein are the following embodiments:

Unless defined otherwise, all terms of art, notations and other technical and scientific terms or terminology used herein are intended to have the same meaning as is commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and/or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a substantial difference over what is generally understood in the art.

Throughout this application, various embodiments may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

As used in the specification and claims, the singular forms “a”, “an” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a sample” includes a plurality of samples, including mixtures thereof.

The terms “determining,” “measuring,” “evaluating,” “assessing,” “assaying,” and “analyzing” are often used interchangeably herein to refer to forms of measurement. The terms include determining if an element is present or not (for example, detection). These terms can include quantitative, qualitative or quantitative and qualitative determinations. Assessing can be relative or absolute. “Detecting the presence of” can include determining the amount of something present in addition to determining whether it is present or absent depending on the context.

The terms “subject,” and “patient” may be used interchangeably herein. A “subject” can be a biological entity containing expressed genetic materials. The biological entity can be a plant, animal, or microorganism, including, for example, bacteria, viruses, fungi, and protozoa. The subject can be a mammal. The mammal can be a human. The subject may be diagnosed or suspected of being at high risk for a disease. In some cases, the subject is not necessarily diagnosed or suspected of being at high risk for the disease.

As used herein, the term “about” a number refers to that number plus or minus 10% of that number. The term “about” a range refers to that range minus 10% of its lowest value and plus 10% of its greatest value.

As used herein, the terms “treatment” or “treating” are used in reference to a pharmaceutical or other intervention regimen for obtaining beneficial or desired results in the recipient. Beneficial or desired results include but are not limited to a therapeutic benefit and/or a prophylactic benefit. A therapeutic benefit may refer to eradication or amelioration of symptoms or of an underlying disorder being treated. Also, a therapeutic benefit can be achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. A prophylactic effect includes delaying, preventing, or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof. For prophylactic benefit, a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease may undergo treatment, even though a diagnosis of this disease may not have been made.

x-y x y 1 The term “C” or “C-C” when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain. For example, the term “C-6alkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from 1 to 6 carbons.

x-y x-y The terms “Calkenyl” and “Calkynyl” refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively.

The term “carbocycle” as used herein refers to a saturated, unsaturated or aromatic ring in which each atom of the ring is carbon. Carbocycle includes 3- to 10-membered monocyclic rings, 5- to 12-membered bicyclic rings, 5- to 12-membered spiro bicycles, and 5- to 12-membered bridged rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. A bicyclic carbocycle includes any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits. A bicyclic carbocycle further includes spiro bicyclic rings such as spiropentane. A bicyclic carbocycle includes any combination of ring sizes such as 3-3 spiro ring systems, 4-4 spiro ring systems, 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, naphthyl, and bicyclo[1.1.1]pentanyl.

The term “aryl” refers to an aromatic monocyclic or aromatic multicyclic hydrocarbon ring system. The aromatic monocyclic or aromatic multicyclic hydrocarbon ring system contains only hydrogen and carbon and from five to eighteen carbon atoms, where at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) π-electron system in accordance with the Hückel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene.

The term “cycloalkyl” refers to a saturated ring in which each atom of the ring is carbon. Cycloalkyl may include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 5- to 12-membered bicyclic rings, 5- to 12-membered spiro bicycles, and 5- to 12-membered bridged rings. In certain embodiments, a cycloalkyl comprises three to ten carbon atoms. In other embodiments, a cycloalkyl comprises five to seven carbon atoms. The cycloalkyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, spiropentane, norbornyl (i.e., bicyclo[2.2.1]heptanyl), decalinyl, 7,7 dimethyl bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, and the like.

The term “cycloalkenyl” refers to a saturated ring in which each atom of the ring is carbon and there is at least one double bond between two ring carbons. Cycloalkenyl may include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 5- to 12-membered bridged rings. In other embodiments, a cycloalkenyl comprises five to seven carbon atoms. The cycloalkenyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

The term “halo” or, alternatively, “halogen” or “halide,” means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

The term “haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-chloromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the haloalkyl radical is optionally further substituted as described herein.

The term “heterocycle” as used herein refers to a saturated, unsaturated or aromatic ring comprising one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycles include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, 5- to 12-membered spiro bicycles, and 5- to 12-membered bridged rings. A bicyclic heterocycle includes any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits. In an exemplary embodiment, an aromatic ring, e.g., pyridyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, morpholine, piperidine or cyclohexene. A bicyclic heterocycle includes any combination of ring sizes such as 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems. A bicyclic heterocycle further includes spiro bicyclic rings, e.g., 5 to 12-membered spiro bicycles, such as 2-oxa-6-azaspiro[3.3]heptane.

The term “heteroaryl” refers to a radical derived from a 5 to 18 membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, the heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) π-electron system in accordance with the Hückel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7] cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano 5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a, 7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e. thienyl).

The term “heterocycloalkyl” refers to a saturated ring with carbon atoms and at least one heteroatom. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycloalkyl may include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, 5- to 12-membered spiro bicycles, and 5- to 12-membered bridged rings. The heteroatoms in the heterocycloalkyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocycloalkyl is attached to the rest of the molecule through any atom of the heterocycloalkyl, valence permitting, such as any carbon or nitrogen atoms of the heterocycloalkyl. Examples of heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 2-oxa-6-azaspiro[3.3]heptane, and 1,1-dioxo-thiomorpholinyl.

The term “heterocycloalkenyl” refers to an unsaturated ring with carbon atoms and at least one heteroatom and there is at least one double bond between two ring carbons. Heterocycloalkenyl does not include heteroaryl rings. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycloalkenyl may include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 5- to 12-membered bridged rings. In other embodiments, a heterocycloalkenyl comprises five to seven ring atoms. The heterocycloalkenyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyls include, e.g., pyrroline (dihydropyrrole), pyrazoline (dihydropyrazole), imidazoline (dihydroimidazole), triazoline (dihydrotriazole), dihydrofuran, dihydrothiophene, oxazoline (dihydrooxazole), isoxazoline (dihydroisoxazole), thiazoline (dihydrothiazole), isothiazoline (dihydroisothiazole), oxadiazoline (dihydrooxadiazole), thiadiazoline (dihydrothiadiazole), dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine.

2 The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., an NH or NHof a compound. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. In certain embodiments, substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds.

2 2 2 2 2 t t t 2 2 2 2 2 2 t t t t 2 2 2 2 2 2 t t t 2 b a b a b a b a b a b a b a b a b b a b a a b a a b a a b a b a b a b a b a b a b c a b a b a b a b a b c a b a a b a a b a a b a b a b a a a b a b c a b a b a b a b a b a b a b c a b a a b a a b a a b a b a b a b c In some embodiments, substituents may include any substituents described herein, for example: halogen, hydroxy, oxo (═O), thioxo (═S), cyano (—CN), nitro (—NO2), imino (═N—H), oximo (═N—OH), hydrazino (=N—NH), —ROR, —ROC(O)R, —ROC(O) OR, —ROC(O)N(R), —RN(R), —RC(O)R, —RC(O)OR, —RC(O)N(R), —RORC(O)N(R), —RN(R)C(O)OR, —RN(R) C(O)R, —RN(R)S(O)R(where t is 1 or 2), —RS(O)R(where t is 1 or 2), —RS(O), OR(where t is 1 or 2), and —RS(O)N(R)(where t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (═O), thioxo (═S), cyano (—CN), nitro (—NO2), imino (═N—H), oximo (═N—OH), hydrazine (=N—NH), —ROR, —ROC(O)R, —ROC(O) OR, —RO(O)N(R), —RN(R), —RC(O)R, —RC(O)OR, —RC(O)N(R), —ROR(O)N(R), —RN(R)C(O)OR, —RN(R) C(O)R, —RN(R)S(O)R(where t is 1 or 2), —RS(O)R(where t is 1 or 2), —RS(O)OR(where t is 1 or 2) and —RS(O)N(R)(where t is 1 or 2); wherein each Ris independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein each R, valence permitting, may be optionally substituted with alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (═O), thioxo (═S), cyano (—CN), nitro (—NO2), imino (═N—H), oximo (═N—OH), hydrazine (=N—NH), —ROR, —RO(O)R, —ROC(O) OR, —ROC(O)N(R), —RN(R), —RC(O)R, —RC(O)OR, —RC(O)N(R), —ROR(O)N(R), —RN(R)C(O)OR, —RN(R) C(O)R, —RN(R)S(O)R(where t is 1 or 2), —RS(O)R(where t is 1 or 2), —RS(O) OR(where t is 1 or 2) and —RS(O)N(R)(where t is 1 or 2); and wherein each Ris independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain, and each Ris a straight or branched alkylene, alkenylene or alkynylene chain.

Double bonds to oxygen atoms, such as oxo groups, are represented herein as both “=O” and “(O)”. Double bonds to nitrogen atoms are represented as both “=NR” and “(NR)”. Double bonds to sulfur atoms are represented as both “=S” and “(S)”.

In some embodiments, a “derivative” polypeptide or peptide is one that is modified, for example, by glycosylation, pegylation, phosphorylation, sulfation, reduction/alkylation, acylation, chemical coupling, or mild formalin treatment. A derivative may also be modified to contain a detectable label, either directly or indirectly, including, but not limited to, a radioisotope, fluorescent, and enzyme label.

Some embodiments refer to nucleic acid sequence information. It is contemplated that in some embodiments, thymine (T) may be interchanged with uracil (U), or vice versa. For example, some sequences in the sequence listing may recite Ts, but these may be replaced with Us in some embodiments. In some oligonucleotides with nucleic acid sequences that include uracil, the uracil may be replaced with thymine. Similarly, in some oligonucleotides with nucleic acid sequences that include thymine, the thymine may be replaced with uracil. In some embodiments, an oligonucleotide such as an siRNA comprises or consists of RNA. In some embodiments, the oligonucleotide may comprise or consist of DNA. For example, an ASO may include DNA.

Some aspects include sequences with nucleotide modifications or modified internucleoside linkages. Generally, and unless otherwise specified, Nf (e.g. Af, Cf, Gf, Tf, or Uf) refers to a 2′-fluoro-modified nucleoside, dN (e.g. dA, dC, dG, dT, or dU) refers to a 2′-deoxy nucleoside, n (e.g. a, c, g, t, or u) refers to a 2′-O-methyl modified nucleoside, and “s” refers to a phosphorothioate linkage.

The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

Variants in MTRES1 were evaluated for associations with dementia, Alzheimer's disease and related traits in 452,401 individuals with genotype data from the UK Biobank cohort. rs117058816 is a rare (AAF=0.006) splice donor variant (c.3+1G>A) in MTRES1. This variant is considered to be a loss-of-function variant that results in a loss or change in the abundance or activity of the MTRES1 gene product.

The analyses resulted in identification of dementia and Alzheimer's disease-related associations for the MTRES1 c.3+1G>A variant. For example, c.3+1G>A was associated with decreased risk of Alzheimer's disease, dementia, delirium, and vascular dementia. c.3+1G>A was also associated with decreased risk of family history of Alzheimer's disease and decreased risk of dementia medication use (Table 2A-2B).

TABLE 2A MTRES1 Dementia, Alzheimer's and related trait associations Alzheimer's Disease Family History of Alzheimer's (n = 2,864) Disease (n = 53,344) Variant Gene Function AAF P value OR P value OR rs117058816 MTRES1 Splice donor; c.3 + 1G > A 0.006 2.58E−04 ↓0.459 9.54E−03 ↓0.893

TABLE 2B MTRES1 Dementia, Alzheimer's and related trait associations Dementia Anticholinesterase Delirium Vascular Dementia (n = 4,009) Medication (n = 813) (n = 3,901) (n = 807) Variant P value OR P value OR P value OR P value OR rs117058816 7.92E−07 ↓0.489 8.04E−03 ↓0.613 7.75E−03 ↓0.667 7.44E−04 ↓0.208

These results indicate that loss or change of function of MTRES1 results in protection from dementia and Alzheimer's disease and related diseases. These results further indicate that therapeutic modulation of MTRES1 may result in similar disease-protective effects.

Screening sets were defined based on bioinformatic analysis. Therapeutic siRNAs were designed to target human MTRES1, and the MTRES1 sequence of at least one toxicology-relevant species, in this case, the non-human primates (NHP) rhesus and cynomolgus monkeys. Drivers for the design of the screening set were predicted specificity of the siRNAs against the transcriptome of the relevant species as well as cross-reactivity between species. Predicted specificity in human, rhesus monkey, cynomolgus monkey, mouse and rat was determined for sense(S) and antisense (AS) strands. These were assigned a “specificity score” which considers the likelihood of unintended downregulation of any other transcript by full or partial complementarity of an siRNA strand (up to 4 mismatches within positions 2-18) as well as the number and positions of mismatches. Thus, off-target(s) for antisense and sense strands of each siRNA were identified. In addition, the number of potential off-targets was used as an additional specificity factor in the specificity score. As identified, siRNAs with high specificity and a low number of predicted off-targets provide a benefit of increased targeting specificity.

In addition to selecting siRNA sequences with high sequence specificity to MTRES1 mRNA, siRNA sequences within the seed region were analyzed for similarity to seed regions of known miRNAs. siRNAs can function in a miRNA like manner via base-pairing with complementary sequences within the 3′-UTR of mRNA molecules. The complementarity typically encompasses the 5′-bases at positions 2-7 of the miRNA (seed region). To circumvent siRNAs to act via functional miRNA binding sites, siRNA strands containing natural miRNA seed regions were avoided. Seed regions identified in miRNAs from human, mouse, rat, rhesus monkey, dog, rabbit and pig are referred to as “conserved”. Combining the “specificity score” with miRNA seed analysis yielded a “specificity category”. This is divided into categories 1-4, with 1 having the highest specificity and 4 having the lowest specificity. Each strand of the siRNA is assigned to a specificity category.

Specificity and species cross-reactivity was assessed for human, cynomolgus monkey, rhesus monkey, mouse and rat MTRES1. The analysis was based on a canonical siRNA design using 19 bases and 17 bases (without considering positions 1 and 19) for cross-reactivity. Full match as well as single mismatch analyses were included.

Analysis of the human Single Nucleotide Polymorphism (SNP) database (NCBI-DB-SNP) to identify siRNAs targeting regions with known SNPs was also carried out to identify siRNAs that may be non-functional in individuals containing the SNP. Information regarding the positions of SNPs within the target sequence as well as minor allele frequency (MAF) in case data was obtained in this analysis.

Initial analysis of the relevant MTRES1 mRNA sequence revealed few sequences that fulfil the specificity parameters and at the same time target MTRES1 mRNA in all of the analyzed relevant species. Therefore, it was decided to design independent screening subsets for the therapeutic siRNAs.

The siRNAs in these subsets recognize the human, cynomolgus monkey, rhesus monkey MTRES1 sequences. Therefore, the siRNAs in these subsets can be used to target human MTRES1 in a therapeutic setting.

The number of siRNA sequences that can be derived from human MTRES1 mRNA (ENST00000311381.8, SEQ ID NO: 2443) without consideration of specificity or species cross-reactivity was 1140 (sense and antisense strand sequences included in SEQ ID NOS: 1-2280).

Prioritizing sequences for target specificity, species cross-reactivity, miRNA seed region sequences and SNPs as described above yields subset A. Subset A contains 82 siRNAs whose base sequences are shown in Table 3.

TABLE 3 Sequences in siRNA subset A SEQ SEQ siRNA ID sense strand  ID antisense strand  Name NO: sequence (5′-3′) NO: sequence (5′-3′) siRNA 78 78 UAAGCGCCAUGGCUAUGGC 1218 GCCAUAGCCAUGGCGCUUA siRNA 81 81 GCGCCAUGGCUAUGGCUAG 1221 CUAGCCAUAGCCAUGGCGC siRNA 87 87 UGGCUAUGGCUAGUGUUAA 1227 UUAACACUAGCCAUAGCCA siRNA 154 154 GGGUGUUCUCCGAGGGACA 1294 UGUCCCUCGGAGAACACCC siRNA 156 156 GUGUUCUCCGAGGGACACC 1296 GGUGUCCCUCGGAGAACAC siRNA 158 158 GUUCUCCGAGGGACACCUU 1298 AAGGUGUCCCUCGGAGAAC siRNA 178 178 AUCAUACAAACUCUGUACU 1318 AGUACAGAGUUUGUAUGAU siRNA 182 182 UACAAACUCUGUACUUCCU 1322 AGGAAGUACAGAGUUUGUA siRNA 190 190 CUGUACUUCCUGGAAUCGA 1330 UCGAUUCCAGGAAGUACAG siRNA 191 191 UGUACUUCCUGGAAUCGAU 1331 AUCGAUUCCAGGAAGUACA siRNA 192 192 GUACUUCCUGGAAUCGAUA 1332 UAUCGAUUCCAGGAAGUAC siRNA 193 193 UACUUCCUGGAAUCGAUAC 1333 GUAUCGAUUCCAGGAAGUA siRNA 194 194 ACUUCCUGGAAUCGAUACU 1334 AGUAUCGAUUCCAGGAAGU siRNA 195 195 CUUCCUGGAAUCGAUACUU 1335 AAGUAUCGAUUCCAGGAAG siRNA 197 197 UCCUGGAAUCGAUACUUGU 1337 ACAAGUAUCGAUUCCAGGA siRNA 198 198 CCUGGAAUCGAUACUUGUA 1338 UACAAGUAUCGAUUCCAGG siRNA 199 199 CUGGAAUCGAUACUUGUAU 1339 AUACAAGUAUCGAUUCCAG siRNA 202 202 GAAUCGAUACUUGUAUUUU 1342 AAAAUACAAGUAUCGAUUC siRNA 220 220 UUCUAGUACCAAGUUACGU 1360 ACGUAACUUGGUACUAGAA siRNA 222 222 CUAGUACCAAGUUACGUGC 1362 GCACGUAACUUGGUACUAG siRNA 223 223 UAGUACCAAGUUACGUGCA 1363 UGCACGUAACUUGGUACUA siRNA 224 224 AGUACCAAGUUACGUGCAC 1364 GUGCACGUAACUUGGUACU siRNA 225 225 GUACCAAGUUACGUGCACC 1365 GGUGCACGUAACUUGGUAC siRNA 226 226 UACCAAGUUACGUGCACCA 1366 UGGUGCACGUAACUUGGUA siRNA 227 227 ACCAAGUUACGUGCACCAA 1367 UUGGUGCACGUAACUUGGU siRNA 228 228 CCAAGUUACGUGCACCAAA 1368 UUUGGUGCACGUAACUUGG siRNA 229 229 CAAGUUACGUGCACCAAAU 1369 AUUUGGUGCACGUAACUUG siRNA 230 230 AAGUUACGUGCACCAAAUU 1370 AAUUUGGUGCACGUAACUU siRNA 231 231 AGUUACGUGCACCAAAUUA 1371 UAAUUUGGUGCACGUAACU siRNA 232 232 GUUACGUGCACCAAAUUAU 1372 AUAAUUUGGUGCACGUAAC siRNA 233 233 UUACGUGCACCAAAUUAUA 1373 UAUAAUUUGGUGCACGUAA siRNA 235 235 ACGUGCACCAAAUUAUAAA 1375 UUUAUAAUUUGGUGCACGU siRNA 331 331 AAGACUCAAAAGUAAUAUA 1471 UAUAUUACUUUUGAGUCUU siRNA 358 358 AAAAUCUACUAAAAAGUCU 1498 AGACUUUUUAGUAGAUUUU siRNA 360 360 AAUCUACUAAAAAGUCUCU 1500 AGAGACUUUUUAGUAGAUU siRNA 361 361 AUCUACUAAAAAGUCUCUG 1501 CAGAGACUUUUUAGUAGAU siRNA 362 362 UCUACUAAAAAGUCUCUGC 1502 GCAGAGACUUUUUAGUAGA siRNA 528 528 UGAAGACGGGGCUAGAUAU 1668 AUAUCUAGCCCCGUCUUCA siRNA 534 534 CGGGGCUAGAUAUUGGGAG 1674 CUCCCAAUAUCUAGCCCCG siRNA 539 539 CUAGAUAUUGGGAGAAACA 1679 UGUUUCUCCCAAUAUCUAG siRNA 619 619 AAGCAGAACGGUGAAAGUG 1759 CACUUUCACCGUUCUGCUU siRNA 620 620 AGCAGAACGGUGAAAGUGG 1760 CCACUUUCACCGUUCUGCU siRNA 621 621 GCAGAACGGUGAAAGUGGG 1761 CCCACUUUCACCGUUCUGC siRNA 632 632 AAAGUGGGAGAUACAUUGG 1772 CCAAUGUAUCUCCCACUUU siRNA 633 633 AAGUGGGAGAUACAUUGGA 1773 UCCAAUGUAUCUCCCACUU siRNA 634 634 AGUGGGAGAUACAUUGGAU 1774 AUCCAAUGUAUCUCCCACU siRNA 636 636 UGGGAGAUACAUUGGAUCU 1776 AGAUCCAAUGUAUCUCCCA siRNA 642 642 AUACAUUGGAUCUUCUCAU 1782 AUGAGAAGAUCCAAUGUAU siRNA 645 645 CAUUGGAUCUUCUCAUUGG 1785 CCAAUGAGAAGAUCCAAUG siRNA 646 646 AUUGGAUCUUCUCAUUGGA 1786 UCCAAUGAGAAGAUCCAAU siRNA 647 647 UUGGAUCUUCUCAUUGGAG 1787 CUCCAAUGAGAAGAUCCAA siRNA 648 648 UGGAUCUUCUCAUUGGAGA 1788 UCUCCAAUGAGAAGAUCCA siRNA 650 650 GAUCUUCUCAUUGGAGAGG 1790 CCUCUCCAAUGAGAAGAUC siRNA 654 654 UUCUCAUUGGAGAGGAUAA 1794 UUAUCCUCUCCAAUGAGAA siRNA 656 656 CUCAUUGGAGAGGAUAAAG 1796 CUUUAUCCUCUCCAAUGAG siRNA 687 687 AGACAGUUAUGCGGAUUCU 1827 AGAAUCCGCAUAACUGUCU siRNA 688 688 GACAGUUAUGCGGAUUCUC 1828 GAGAAUCCGCAUAACUGUC siRNA 690 690 CAGUUAUGCGGAUUCUCUU 1830 AAGAGAAUCCGCAUAACUG siRNA 693 693 UUAUGCGGAUUCUCUUGAA 1833 UUCAAGAGAAUCCGCAUAA siRNA 694 694 UAUGCGGAUUCUCUUGAAA 1834 UUUCAAGAGAAUCCGCAUA siRNA 695 695 AUGCGGAUUCUCUUGAAAA 1835 UUUUCAAGAGAAUCCGCAU siRNA 745 745 AUACAGAGUGGUGUUACGG 1885 CCGUAACACCACUCUGUAU siRNA 746 746 UACAGAGUGGUGUUACGGC 1886 GCCGUAACACCACUCUGUA siRNA 748 748 CAGAGUGGUGUUACGGCGG 1888 CCGCCGUAACACCACUCUG siRNA 749 749 AGAGUGGUGUUACGGCGGU 1889 ACCGCCGUAACACCACUCU siRNA 751 751 AGUGGUGUUACGGCGGUGG 1891 CCACCGCCGUAACACCACU siRNA 752 752 GUGGUGUUACGGCGGUGGA 1892 UCCACCGCCGUAACACCAC siRNA 753 753 UGGUGUUACGGCGGUGGAA 1893 UUCCACCGCCGUAACACCA siRNA 754 754 GGUGUUACGGCGGUGGAAA 1894 UUUCCACCGCCGUAACACC siRNA 755 755 GUGUUACGGCGGUGGAAAA 1895 UUUUCCACCGCCGUAACAC siRNA 756 756 UGUUACGGCGGUGGAAAAG 1896 CUUUUCCACCGCCGUAACA siRNA 757 757 GUUACGGCGGUGGAAAAGU 1897 ACUUUUCCACCGCCGUAAC siRNA 758 758 UUACGGCGGUGGAAAAGUU 1898 AACUUUUCCACCGCCGUAA siRNA 759 759 UACGGCGGUGGAAAAGUUU 1899 AAACUUUUCCACCGCCGUA siRNA 761 761 CGGCGGUGGAAAAGUUUAA 1901 UUAAACUUUUCCACCGCCG siRNA 773 773 AGUUUAAAGUUGCCUAAGA 1913 UCUUAGGCAACUUUAAACU siRNA 775 775 UUUAAAGUUGCCUAAGAAG 1915 CUUCUUAGGCAACUUUAAA siRNA 808 808 AAUGGAUUGCUUUUUAGCA 1948 UGCUAAAAAGCAAUCCAUU siRNA 810 810 UGGAUUGCUUUUUAGCAAU 1950 AUUGCUAAAAAGCAAUCCA siRNA 852 852 GAAGGGGUCACCUGAAAAA 1992 UUUUUCAGGUGACCCCUUC siRNA 853 853 AAGGGGUCACCUGAAAAAU 1993 AUUUUUCAGGUGACCCCUU siRNA 887 887 AAAUAAAGUUCUCUUAGCG 2027 CGCUAAGAGAACUUUAUUU

Cross-reactivity: With 19mer in human MTRES1 mRNA, with 17mer/19mer in NHP MTRES1 Specificity category: For human and NHP: AS2 or better, SS3 or better miRNA seeds: AS+SS strand: seed region not conserved in human, mouse, and rat and not present in >4 species Off-target frequency: ≤20 human off-targets matched with 2 mismatches in antisense strand SNPs: siRNA target sites do not harbor SNPs with a MAF≥1% (pos. 2-18) The siRNAs in subset A have the following characteristics:

The siRNA sequences in subset A were selected for more stringent specificity to yield subset B. Subset B includes 73 siRNAs whose base sequences are shown in Table 4.

TABLE 4 Sequences in siRNA subset B SEQ ID sense strand  SEQ ID antisense strand  NO: sequence (5′-3′) NO: sequence (5′-3′) 78 UAAGCGCCAUGGCUAUGGC 1218 GCCAUAGCCAUGGCGCUUA 81 GCGCCAUGGCUAUGGCUAG 1221 CUAGCCAUAGCCAUGGCGC 87 UGGCUAUGGCUAGUGUUAA 1227 UUAACACUAGCCAUAGCCA 154 GGGUGUUCUCCGAGGGACA 1294 UGUCCCUCGGAGAACACCC 156 GUGUUCUCCGAGGGACACC 1296 GGUGUCCCUCGGAGAACAC 158 GUUCUCCGAGGGACACCUU 1298 AAGGUGUCCCUCGGAGAAC 178 AUCAUACAAACUCUGUACU 1318 AGUACAGAGUUUGUAUGAU 182 UACAAACUCUGUACUUCCU 1322 AGGAAGUACAGAGUUUGUA 190 CUGUACUUCCUGGAAUCGA 1330 UCGAUUCCAGGAAGUACAG 191 UGUACUUCCUGGAAUCGAU 1331 AUCGAUUCCAGGAAGUACA 192 GUACUUCCUGGAAUCGAUA 1332 UAUCGAUUCCAGGAAGUAC 193 UACUUCCUGGAAUCGAUAC 1333 GUAUCGAUUCCAGGAAGUA 195 CUUCCUGGAAUCGAUACUU 1335 AAGUAUCGAUUCCAGGAAG 197 UCCUGGAAUCGAUACUUGU 1337 ACAAGUAUCGAUUCCAGGA 198 CCUGGAAUCGAUACUUGUA 1338 UACAAGUAUCGAUUCCAGG 199 CUGGAAUCGAUACUUGUAU 1339 AUACAAGUAUCGAUUCCAG 202 GAAUCGAUACUUGUAUUUU 1342 AAAAUACAAGUAUCGAUUC 220 UUCUAGUACCAAGUUACGU 1360 ACGUAACUUGGUACUAGAA 222 CUAGUACCAAGUUACGUGC 1362 GCACGUAACUUGGUACUAG 223 UAGUACCAAGUUACGUGCA 1363 UGCACGUAACUUGGUACUA 224 AGUACCAAGUUACGUGCAC 1364 GUGCACGUAACUUGGUACU 225 GUACCAAGUUACGUGCACC 1365 GGUGCACGUAACUUGGUAC 226 UACCAAGUUACGUGCACCA 1366 UGGUGCACGUAACUUGGUA 227 ACCAAGUUACGUGCACCAA 1367 UUGGUGCACGUAACUUGGU 228 CCAAGUUACGUGCACCAAA 1368 UUUGGUGCACGUAACUUGG 229 CAAGUUACGUGCACCAAAU 1369 AUUUGGUGCACGUAACUUG 230 AAGUUACGUGCACCAAAUU 1370 AAUUUGGUGCACGUAACUU 231 AGUUACGUGCACCAAAUUA 1371 UAAUUUGGUGCACGUAACU 232 GUUACGUGCACCAAAUUAU 1372 AUAAUUUGGUGCACGUAAC 233 UUACGUGCACCAAAUUAUA 1373 UAUAAUUUGGUGCACGUAA 235 ACGUGCACCAAAUUAUAAA 1375 UUUAUAAUUUGGUGCACGU 358 AAAAUCUACUAAAAAGUCU 1498 AGACUUUUUAGUAGAUUUU 360 AAUCUACUAAAAAGUCUCU 1500 AGAGACUUUUUAGUAGAUU 362 UCUACUAAAAAGUCUCUGC 1502 GCAGAGACUUUUUAGUAGA 528 UGAAGACGGGGCUAGAUAU 1668 AUAUCUAGCCCCGUCUUCA 534 CGGGGCUAGAUAUUGGGAG 1674 CUCCCAAUAUCUAGCCCCG 539 CUAGAUAUUGGGAGAAACA 1679 UGUUUCUCCCAAUAUCUAG 619 AAGCAGAACGGUGAAAGUG 1759 CACUUUCACCGUUCUGCUU 620 AGCAGAACGGUGAAAGUGG 1760 CCACUUUCACCGUUCUGCU 621 GCAGAACGGUGAAAGUGGG 1761 CCCACUUUCACCGUUCUGC 632 AAAGUGGGAGAUACAUUGG 1772 CCAAUGUAUCUCCCACUUU 633 AAGUGGGAGAUACAUUGGA 1773 UCCAAUGUAUCUCCCACUU 636 UGGGAGAUACAUUGGAUCU 1776 AGAUCCAAUGUAUCUCCCA 642 AUACAUUGGAUCUUCUCAU 1782 AUGAGAAGAUCCAAUGUAU 645 CAUUGGAUCUUCUCAUUGG 1785 CCAAUGAGAAGAUCCAAUG 647 UUGGAUCUUCUCAUUGGAG 1787 CUCCAAUGAGAAGAUCCAA 648 UGGAUCUUCUCAUUGGAGA 1788 UCUCCAAUGAGAAGAUCCA 654 UUCUCAUUGGAGAGGAUAA 1794 UUAUCCUCUCCAAUGAGAA 656 CUCAUUGGAGAGGAUAAAG 1796 CUUUAUCCUCUCCAAUGAG 687 AGACAGUUAUGCGGAUUCU 1827 AGAAUCCGCAUAACUGUCU 688 GACAGUUAUGCGGAUUCUC 1828 GAGAAUCCGCAUAACUGUC 690 CAGUUAUGCGGAUUCUCUU 1830 AAGAGAAUCCGCAUAACUG 693 UUAUGCGGAUUCUCUUGAA 1833 UUCAAGAGAAUCCGCAUAA 694 UAUGCGGAUUCUCUUGAAA 1834 UUUCAAGAGAAUCCGCAUA 695 AUGCGGAUUCUCUUGAAAA 1835 UUUUCAAGAGAAUCCGCAU 745 AUACAGAGUGGUGUUACGG 1885 CCGUAACACCACUCUGUAU 746 UACAGAGUGGUGUUACGGC 1886 GCCGUAACACCACUCUGUA 748 CAGAGUGGUGUUACGGCGG 1888 CCGCCGUAACACCACUCUG 749 AGAGUGGUGUUACGGCGGU 1889 ACCGCCGUAACACCACUCU 751 AGUGGUGUUACGGCGGUGG 1891 CCACCGCCGUAACACCACU 752 GUGGUGUUACGGCGGUGGA 1892 UCCACCGCCGUAACACCAC 753 UGGUGUUACGGCGGUGGAA 1893 UUCCACCGCCGUAACACCA 754 GGUGUUACGGCGGUGGAAA 1894 UUUCCACCGCCGUAACACC 755 GUGUUACGGCGGUGGAAAA 1895 UUUUCCACCGCCGUAACAC 756 UGUUACGGCGGUGGAAAAG 1896 CUUUUCCACCGCCGUAACA 757 GUUACGGCGGUGGAAAAGU 1897 ACUUUUCCACCGCCGUAAC 758 UUACGGCGGUGGAAAAGUU 1898 AACUUUUCCACCGCCGUAA 759 UACGGCGGUGGAAAAGUUU 1899 AAACUUUUCCACCGCCGUA 761 CGGCGGUGGAAAAGUUUAA 1901 UUAAACUUUUCCACCGCCG 773 AGUUUAAAGUUGCCUAAGA 1913 UCUUAGGCAACUUUAAACU 808 AAUGGAUUGCUUUUUAGCA 1948 UGCUAAAAAGCAAUCCAUU 852 GAAGGGGUCACCUGAAAAA 1992 UUUUUCAGGUGACCCCUUC 853 AAGGGGUCACCUGAAAAAU 1993 AUUUUUCAGGUGACCCCUU

Cross-reactivity: With 19mer in human MTRES1 mRNA, with 17mer/19mer in NHP MTRES1 Specificity category: For human and NHP: AS2 or better, SS3 or better miRNA seeds: AS+SS strand: seed region not conserved in human, mouse, and rat and not present in >4 species Off-target frequency: ≤15 human off-targets matched with 2 mismatches in antisense strand SNPs: siRNA target sites do not harbor SNPs with a MAF≥1% (pos. 2-18) The siRNAs in subset B have the following characteristics:

The siRNA sequences in subset B were further selected for absence of seed regions in the AS strand that are identical to a seed region of known human miRNA to yield subset C. Subset C includes 54 siRNAs whose base sequences are shown in Table 5.

TABLE 5 Sequences in siRNA subset C SEQ ID sense strand  SEQ ID antisense strand  NO: sequence (5′-3′) NO: sequence (5′-3′) 78 UAAGCGCCAUGGCUAUGGC 1218 GCCAUAGCCAUGGCGCUUA 87 UGGCUAUGGCUAGUGUUAA 1227 UUAACACUAGCCAUAGCCA 154 GGGUGUUCUCCGAGGGACA 1294 UGUCCCUCGGAGAACACCC 158 GUUCUCCGAGGGACACCUU 1298 AAGGUGUCCCUCGGAGAAC 178 AUCAUACAAACUCUGUACU 1318 AGUACAGAGUUUGUAUGAU 182 UACAAACUCUGUACUUCCU 1322 AGGAAGUACAGAGUUUGUA 190 CUGUACUUCCUGGAAUCGA 1330 UCGAUUCCAGGAAGUACAG 191 UGUACUUCCUGGAAUCGAU 1331 AUCGAUUCCAGGAAGUACA 192 GUACUUCCUGGAAUCGAUA 1332 UAUCGAUUCCAGGAAGUAC 193 UACUUCCUGGAAUCGAUAC 1333 GUAUCGAUUCCAGGAAGUA 195 CUUCCUGGAAUCGAUACUU 1335 AAGUAUCGAUUCCAGGAAG 199 CUGGAAUCGAUACUUGUAU 1339 AUACAAGUAUCGAUUCCAG 202 GAAUCGAUACUUGUAUUUU 1342 AAAAUACAAGUAUCGAUUC 220 UUCUAGUACCAAGUUACGU 1360 ACGUAACUUGGUACUAGAA 222 CUAGUACCAAGUUACGUGC 1362 GCACGUAACUUGGUACUAG 223 UAGUACCAAGUUACGUGCA 1363 UGCACGUAACUUGGUACUA 224 AGUACCAAGUUACGUGCAC 1364 GUGCACGUAACUUGGUACU 225 GUACCAAGUUACGUGCACC 1365 GGUGCACGUAACUUGGUAC 226 UACCAAGUUACGUGCACCA 1366 UGGUGCACGUAACUUGGUA 227 ACCAAGUUACGUGCACCAA 1367 UUGGUGCACGUAACUUGGU 228 CCAAGUUACGUGCACCAAA 1368 UUUGGUGCACGUAACUUGG 229 CAAGUUACGUGCACCAAAU 1369 AUUUGGUGCACGUAACUUG 231 AGUUACGUGCACCAAAUUA 1371 UAAUUUGGUGCACGUAACU 233 UUACGUGCACCAAAUUAUA 1373 UAUAAUUUGGUGCACGUAA 235 ACGUGCACCAAAUUAUAAA 1375 UUUAUAAUUUGGUGCACGU 358 AAAAUCUACUAAAAAGUCU 1498 AGACUUUUUAGUAGAUUUU 528 UGAAGACGGGGCUAGAUAU 1668 AUAUCUAGCCCCGUCUUCA 534 CGGGGCUAGAUAUUGGGAG 1674 CUCCCAAUAUCUAGCCCCG 539 CUAGAUAUUGGGAGAAACA 1679 UGUUUCUCCCAAUAUCUAG 619 AAGCAGAACGGUGAAAGUG 1759 CACUUUCACCGUUCUGCUU 620 AGCAGAACGGUGAAAGUGG 1760 CCACUUUCACCGUUCUGCU 621 GCAGAACGGUGAAAGUGGG 1761 CCCACUUUCACCGUUCUGC 632 AAAGUGGGAGAUACAUUGG 1772 CCAAUGUAUCUCCCACUUU 633 AAGUGGGAGAUACAUUGGA 1773 UCCAAUGUAUCUCCCACUU 636 UGGGAGAUACAUUGGAUCU 1776 AGAUCCAAUGUAUCUCCCA 645 CAUUGGAUCUUCUCAUUGG 1785 CCAAUGAGAAGAUCCAAUG 647 UUGGAUCUUCUCAUUGGAG 1787 CUCCAAUGAGAAGAUCCAA 656 CUCAUUGGAGAGGAUAAAG 1796 CUUUAUCCUCUCCAAUGAG 687 AGACAGUUAUGCGGAUUCU 1827 AGAAUCCGCAUAACUGUCU 688 GACAGUUAUGCGGAUUCUC 1828 GAGAAUCCGCAUAACUGUC 745 AUACAGAGUGGUGUUACGG 1885 CCGUAACACCACUCUGUAU 746 UACAGAGUGGUGUUACGGC 1886 GCCGUAACACCACUCUGUA 748 CAGAGUGGUGUUACGGCGG 1888 CCGCCGUAACACCACUCUG 749 AGAGUGGUGUUACGGCGGU 1889 ACCGCCGUAACACCACUCU 751 AGUGGUGUUACGGCGGUGG 1891 CCACCGCCGUAACACCACU 752 GUGGUGUUACGGCGGUGGA 1892 UCCACCGCCGUAACACCAC 753 UGGUGUUACGGCGGUGGAA 1893 UUCCACCGCCGUAACACCA 755 GUGUUACGGCGGUGGAAAA 1895 UUUUCCACCGCCGUAACAC 756 UGUUACGGCGGUGGAAAAG 1896 CUUUUCCACCGCCGUAACA 759 UACGGCGGUGGAAAAGUUU 1899 AAACUUUUCCACCGCCGUA 761 CGGCGGUGGAAAAGUUUAA 1901 UUAAACUUUUCCACCGCCG 773 AGUUUAAAGUUGCCUAAGA 1913 UCUUAGGCAACUUUAAACU 808 AAUGGAUUGCUUUUUAGCA 1948 UGCUAAAAAGCAAUCCAUU 853 AAGGGGUCACCUGAAAAAU 1993 AUUUUUCAGGUGACCCCUU

Cross-reactivity: With 19mer in human MTRES1 mRNA, with 17mer/19mer in NHP MTRES1 Specificity category: For human and NHP: AS2 or better, SS3 or better miRNA seeds: AS+SS strand: seed region not conserved in human, mouse, and rat and not present in >4 species. AS strand: seed region not identical to seed region of known human miRNA Off-target frequency: ≤15 human off-targets matched with 2 mismatches by antisense strand SNPs: siRNA target sites do not harbor SNPs with a MAF≥1% (pos. 2-18) The siRNAs in subset C have the following characteristics:

The siRNA sequences in subset C were also selected for absence of seed regions in the AS or S strands that are identical to a seed region of known human miRNA to yield subset D. Subset D includes 35 siRNAs whose base sequences are shown in Table 6.

TABLE 6 Sequences in siRNA subset D SEQ ID sense strand  SEQ ID antisense strand  NO: sequence (5′-3′) NO: sequence (5′-3′) 87 UGGCUAUGGCUAGUGUUAA 1227 UUAACACUAGCCAUAGCCA 182 UACAAACUCUGUACUUCCU 1322 AGGAAGUACAGAGUUUGUA 190 CUGUACUUCCUGGAAUCGA 1330 UCGAUUCCAGGAAGUACAG 191 UGUACUUCCUGGAAUCGAU 1331 AUCGAUUCCAGGAAGUACA 193 UACUUCCUGGAAUCGAUAC 1333 GUAUCGAUUCCAGGAAGUA 194 ACUUCCUGGAAUCGAUACU 1334 AGUAUCGAUUCCAGGAAGU 202 GAAUCGAUACUUGUAUUUU 1342 AAAAUACAAGUAUCGAUUC 220 UUCUAGUACCAAGUUACGU 1360 ACGUAACUUGGUACUAGAA 222 CUAGUACCAAGUUACGUGC 1362 GCACGUAACUUGGUACUAG 224 AGUACCAAGUUACGUGCAC 1364 GUGCACGUAACUUGGUACU 225 GUACCAAGUUACGUGCACC 1365 GGUGCACGUAACUUGGUAC 226 UACCAAGUUACGUGCACCA 1366 UGGUGCACGUAACUUGGUA 228 CCAAGUUACGUGCACCAAA 1368 UUUGGUGCACGUAACUUGG 229 CAAGUUACGUGCACCAAAU 1369 AUUUGGUGCACGUAACUUG 231 AGUUACGUGCACCAAAUUA 1371 UAAUUUGGUGCACGUAACU 233 UUACGUGCACCAAAUUAUA 1373 UAUAAUUUGGUGCACGUAA 358 AAAAUCUACUAAAAAGUCU 1498 AGACUUUUUAGUAGAUUUU 361 AUCUACUAAAAAGUCUCUG 1501 CAGAGACUUUUUAGUAGAU 528 UGAAGACGGGGCUAGAUAU 1668 AUAUCUAGCCCCGUCUUCA 539 CUAGAUAUUGGGAGAAACA 1679 UGUUUCUCCCAAUAUCUAG 619 AAGCAGAACGGUGAAAGUG 1759 CACUUUCACCGUUCUGCUU 645 CAUUGGAUCUUCUCAUUGG 1785 CCAAUGAGAAGAUCCAAUG 647 UUGGAUCUUCUCAUUGGAG 1787 CUCCAAUGAGAAGAUCCAA 688 GACAGUUAUGCGGAUUCUC 1828 GAGAAUCCGCAUAACUGUC 745 AUACAGAGUGGUGUUACGG 1885 CCGUAACACCACUCUGUAU 751 AGUGGUGUUACGGCGGUGG 1891 CCACCGCCGUAACACCACU 752 GUGGUGUUACGGCGGUGGA 1892 UCCACCGCCGUAACACCAC 755 GUGUUACGGCGGUGGAAAA 1895 UUUUCCACCGCCGUAACAC 756 UGUUACGGCGGUGGAAAAG 1896 CUUUUCCACCGCCGUAACA 759 UACGGCGGUGGAAAAGUUU 1899 AAACUUUUCCACCGCCGUA 761 CGGCGGUGGAAAAGUUUAA 1901 UUAAACUUUUCCACCGCCG 773 AGUUUAAAGUUGCCUAAGA 1913 UCUUAGGCAACUUUAAACU 775 UUUAAAGUUGCCUAAGAAG 1915 CUUCUUAGGCAACUUUAAA 810 UGGAUUGCUUUUUAGCAAU 1950 AUUGCUAAAAAGCAAUCCA 887 AAAUAAAGUUCUCUUAGCG 2027 CGCUAAGAGAACUUUAUUU

Cross-reactivity: With 19mer in human MTRES1 mRNA, with 17mer/19mer in NHP MTRES1 Specificity category: For human and NHP: AS2 or better, SS3 or better miRNA seeds: AS+SS strand: seed region not conserved in human, mouse, and rat and not present in >4 species. AS+SS strand: seed region not identical to seed region of known human miRNA Off-target frequency: ≤20 human off-targets matched with 2 mismatches by antisense strand SNPs: siRNA target sites do not harbor SNPs with a MAF≥1% (pos. 2-18) The siRNAs in subset D have the following characteristics:

The siRNA sequences in subset D were further selected for more stringent specificity to yield subset E. Subset E includes 30 siRNAs whose base sequences are shown in Table 7.

TABLE 7 Sequences in siRNA subset E SEQ ID sense strand  SEQ ID antisense strand  NO: sequence (5′-3′) NO: sequence (5′-3′) 87 UGGCUAUGGCUAGUGUUAA 1227 UUAACACUAGCCAUAGCCA 182 UACAAACUCUGUACUUCCU 1322 AGGAAGUACAGAGUUUGUA 190 CUGUACUUCCUGGAAUCGA 1330 UCGAUUCCAGGAAGUACAG 191 UGUACUUCCUGGAAUCGAU 1331 AUCGAUUCCAGGAAGUACA 193 UACUUCCUGGAAUCGAUAC 1333 GUAUCGAUUCCAGGAAGUA 202 GAAUCGAUACUUGUAUUUU 1342 AAAAUACAAGUAUCGAUUC 220 UUCUAGUACCAAGUUACGU 1360 ACGUAACUUGGUACUAGAA 222 CUAGUACCAAGUUACGUGC 1362 GCACGUAACUUGGUACUAG 224 AGUACCAAGUUACGUGCAC 1364 GUGCACGUAACUUGGUACU 225 GUACCAAGUUACGUGCACC 1365 GGUGCACGUAACUUGGUAC 226 UACCAAGUUACGUGCACCA 1366 UGGUGCACGUAACUUGGUA 228 CCAAGUUACGUGCACCAAA 1368 UUUGGUGCACGUAACUUGG 229 CAAGUUACGUGCACCAAAU 1369 AUUUGGUGCACGUAACUUG 231 AGUUACGUGCACCAAAUUA 1371 UAAUUUGGUGCACGUAACU 233 UUACGUGCACCAAAUUAUA 1373 UAUAAUUUGGUGCACGUAA 358 AAAAUCUACUAAAAAGUCU 1498 AGACUUUUUAGUAGAUUUU 528 UGAAGACGGGGCUAGAUAU 1668 AUAUCUAGCCCCGUCUUCA 539 CUAGAUAUUGGGAGAAACA 1679 UGUUUCUCCCAAUAUCUAG 619 AAGCAGAACGGUGAAAGUG 1759 CACUUUCACCGUUCUGCUU 645 CAUUGGAUCUUCUCAUUGG 1785 CCAAUGAGAAGAUCCAAUG 647 UUGGAUCUUCUCAUUGGAG 1787 CUCCAAUGAGAAGAUCCAA 688 GACAGUUAUGCGGAUUCUC 1828 GAGAAUCCGCAUAACUGUC 745 AUACAGAGUGGUGUUACGG 1885 CCGUAACACCACUCUGUAU 751 AGUGGUGUUACGGCGGUGG 1891 CCACCGCCGUAACACCACU 752 GUGGUGUUACGGCGGUGGA 1892 UCCACCGCCGUAACACCAC 755 GUGUUACGGCGGUGGAAAA 1895 UUUUCCACCGCCGUAACAC 756 UGUUACGGCGGUGGAAAAG 1896 CUUUUCCACCGCCGUAACA 759 UACGGCGGUGGAAAAGUUU 1899 AAACUUUUCCACCGCCGUA 761 CGGCGGUGGAAAAGUUUAA 1901 UUAAACUUUUCCACCGCCG 773 AGUUUAAAGUUGCCUAAGA 1913 UCUUAGGCAACUUUAAACU

Cross-reactivity: With 19mer in human MTRES1 mRNA, with 17mer/19mer in NHP MTRES1 Specificity category: For human and NHP: AS2 or better, SS3 or better miRNA seeds: AS+SS strand: seed region not conserved in human, mouse, and rat and not present in >4 species. AS+SS strand: seed region not identical to seed region of known human miRNA Off-target frequency: ≤15 human off-targets matched with 2 mismatches by antisense strand SNPs: siRNA target sites do not harbor SNPs with a MAF≥1% (pos. 2-18) The siRNAs in subset E have the following characteristics:

Subset F includes 54 siRNAs. The siRNAs in subset F include siRNAs from subset A, and are included in Table 8. In some cases, the sense strand of any of the siRNAs of subset F comprises modification pattern 6S (Table 9). In some cases, the antisense strand of any of the siRNAs of subset F comprises modification pattern 7AS (Table 9, “subset G”). In some cases, the sense strand of any of the siRNAs of subset F contains an alternative modification pattern (Table 10, “subset H”). In some cases, the antisense strand of any of the siRNAs of subset F comprises modification pattern 7AS (Table 10). The siRNAs in subset F may comprise any other modification pattern(s). In Table 9 and Table 10, Nf (e.g. Af, Cf, Gf, Tf, or Uf) is a 2′-fluoro-modified nucleoside, n (e.g. a, c, g, t, or u) is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate linkage.

TABLE 8 Sequences in siRNA subset F SEQ ID sense strand  SEQ ID antisense strand  NO: sequence (5′-3′) NO: sequence (5′-3′) 87 UGGCUAUGGCUAGUGUUAA 1227 UUAACACUAGCCAUAGCCA 178 AUCAUACAAACUCUGUACU 1318 AGUACAGAGUUUGUAUGAU 190 CUGUACUUCCUGGAAUCGA 1330 UCGAUUCCAGGAAGUACAG 191 UGUACUUCCUGGAAUCGAU 1331 AUCGAUUCCAGGAAGUACA 192 GUACUUCCUGGAAUCGAUA 1332 UAUCGAUUCCAGGAAGUAC 193 UACUUCCUGGAAUCGAUAC 1333 GUAUCGAUUCCAGGAAGUA 195 CUUCCUGGAAUCGAUACUU 1335 AAGUAUCGAUUCCAGGAAG 199 CUGGAAUCGAUACUUGUAU 1339 AUACAAGUAUCGAUUCCAG 202 GAAUCGAUACUUGUAUUUU 1342 AAAAUACAAGUAUCGAUUC 222 CUAGUACCAAGUUACGUGC 1362 GCACGUAACUUGGUACUAG 223 UAGUACCAAGUUACGUGCA 1363 UGCACGUAACUUGGUACUA 224 AGUACCAAGUUACGUGCAC 1364 GUGCACGUAACUUGGUACU 225 GUACCAAGUUACGUGCACC 1365 GGUGCACGUAACUUGGUAC 226 UACCAAGUUACGUGCACCA 1366 UGGUGCACGUAACUUGGUA 228 CCAAGUUACGUGCACCAAA 1368 UUUGGUGCACGUAACUUGG 229 CAAGUUACGUGCACCAAAU 1369 AUUUGGUGCACGUAACUUG 230 AAGUUACGUGCACCAAAUU 1370 AAUUUGGUGCACGUAACUU 232 GUUACGUGCACCAAAUUAU 1372 AUAAUUUGGUGCACGUAAC 233 UUACGUGCACCAAAUUAUA 1373 UAUAAUUUGGUGCACGUAA 331 AAGACUCAAAAGUAAUAUA 1471 UAUAUUACUUUUGAGUCUU 358 AAAAUCUACUAAAAAGUCU 1498 AGACUUUUUAGUAGAUUUU 362 UCUACUAAAAAGUCUCUGC 1502 GCAGAGACUUUUUAGUAGA 528 UGAAGACGGGGCUAGAUAU 1668 AUAUCUAGCCCCGUCUUCA 539 CUAGAUAUUGGGAGAAACA 1679 UGUUUCUCCCAAUAUCUAG 620 AGCAGAACGGUGAAAGUGG 1760 CCACUUUCACCGUUCUGCU 632 AAAGUGGGAGAUACAUUGG 1772 CCAAUGUAUCUCCCACUUU 633 AAGUGGGAGAUACAUUGGA 1773 UCCAAUGUAUCUCCCACUU 634 AGUGGGAGAUACAUUGGAU 1774 AUCCAAUGUAUCUCCCACU 636 UGGGAGAUACAUUGGAUCU 1776 AGAUCCAAUGUAUCUCCCA 642 AUACAUUGGAUCUUCUCAU 1782 AUGAGAAGAUCCAAUGUAU 645 CAUUGGAUCUUCUCAUUGG 1785 CCAAUGAGAAGAUCCAAUG 646 AUUGGAUCUUCUCAUUGGA 1786 UCCAAUGAGAAGAUCCAAU 647 UUGGAUCUUCUCAUUGGAG 1787 CUCCAAUGAGAAGAUCCAA 648 UGGAUCUUCUCAUUGGAGA 1788 UCUCCAAUGAGAAGAUCCA 650 GAUCUUCUCAUUGGAGAGG 1790 CCUCUCCAAUGAGAAGAUC 654 UUCUCAUUGGAGAGGAUAA 1794 UUAUCCUCUCCAAUGAGAA 656 CUCAUUGGAGAGGAUAAAG 1796 CUUUAUCCUCUCCAAUGAG 687 AGACAGUUAUGCGGAUUCU 1827 AGAAUCCGCAUAACUGUCU 688 GACAGUUAUGCGGAUUCUC 1828 GAGAAUCCGCAUAACUGUC 693 UUAUGCGGAUUCUCUUGAA 1833 UUCAAGAGAAUCCGCAUAA 694 UAUGCGGAUUCUCUUGAAA 1834 UUUCAAGAGAAUCCGCAUA 695 AUGCGGAUUCUCUUGAAAA 1835 UUUUCAAGAGAAUCCGCAU 746 UACAGAGUGGUGUUACGGC 1886 GCCGUAACACCACUCUGUA 755 GUGUUACGGCGGUGGAAAA 1895 UUUUCCACCGCCGUAACAC 756 UGUUACGGCGGUGGAAAAG 1896 CUUUUCCACCGCCGUAACA 757 GUUACGGCGGUGGAAAAGU 1897 ACUUUUCCACCGCCGUAAC 758 UUACGGCGGUGGAAAAGUU 1898 AACUUUUCCACCGCCGUAA 759 UACGGCGGUGGAAAAGUUU 1899 AAACUUUUCCACCGCCGUA 761 CGGCGGUGGAAAAGUUUAA 1901 UUAAACUUUUCCACCGCCG 773 AGUUUAAAGUUGCCUAAGA 1913 UCUUAGGCAACUUUAAACU 775 UUUAAAGUUGCCUAAGAAG 1915 CUUCUUAGGCAACUUUAAA 810 UGGAUUGCUUUUUAGCAAU 1950 AUUGCUAAAAAGCAAUCCA 852 GAAGGGGUCACCUGAAAAA 1992 UUUUUCAGGUGACCCCUUC 887 AAAUAAAGUUCUCUUAGCG 2027 CGCUAAGAGAACUUUAUUU

TABLE 9 Sequences in siRNA subset G SEQ SEQ ID ID NO: sense strand sequence (5′-3′) NO: antisense strand sequence (5′-3′) 2281 UfsgsGfcUfaUfgGfcUfaGfuGfuUfaAfsusu 2335 usUfsaAfcAfcUfaGfcCfaUfaGfcCfasusu 2282 AfsusCfaUfaCfaAfaCfuCfuGfuAfcAfsusu 2336 usGfsuAfcAfgAfgUfuUfgUfaUfgAfususu 2283 CfsusGfuAfcUfuCfcUfgGfaAfuCfgAfsusu 2337 usCfsgAfuUfcCfaGfgAfaGfuAfcAfgsusu 2284 UfsgsUfaCfuUfcCfuGfgAfaUfcGfaAfsusu 2338 usUfscGfaUfuCfcAfgGfaAfgUfaCfasusu 2285 GfsusAfcUfuCfcUfgGfaAfuCfgAfuAfsusu 2339 usAfsuCfgAfuUfcCfaGfgAfaGfuAfcsusu 2286 UfsasCfuUfcCfuGfgAfaUfcGfaUfaAfsusu 2340 usUfsaUfcGfaUfuCfcAfgGfaAfgUfasusu 2287 CfsusUfcCfuGfgAfaUfcGfaUfaCfuAfsusu 2341 usAfsgUfaUfcGfaUfuCfcAfgGfaAfgsusu 2288 CfsusGfgAfaUfcGfaUfaCfuUfgUfaAfsusu 2342 usUfsaCfaAfgUfaUfcGfaUfuCfcAfgsusu 2289 GfsasAfuCfgAfuAfcUfuGfuAfuUfuAfsusu 2343 usAfsaAfuAfcAfaGfuAfuCfgAfuUfcsusu 2290 CfsusAfgUfaCfcAfaGfuUfaCfgUfgAfsusu 2344 usCfsaCfgUfaAfcUfuGfgUfaCfuAfgsusu 2291 UfsasGfuAfcCfaAfgUfuAfcGfuGfcAfsusu 2345 usGfscAfcGfuAfaCfuUfgGfuAfcUfasusu 2292 AfsgsUfaCfcAfaGfuUfaCfgUfgCfaAfsusu 2346 usUfsgCfaCfgUfaAfcUfuGfgUfaCfususu 2293 GfsusAfcCfaAfgUfuAfcGfuGfcAfcAfsusu 2347 usGfsuGfcAfcGfuAfaCfuUfgGfuAfcsusu 2294 UfsasCfcAfaGfuUfaCfgUfgCfaCfcAfsusu 2348 usGfsgUfgCfaCfgUfaAfcUfuGfgUfasusu 2295 CfscsAfaGfuUfaCfgUfgCfaCfcAfaAfsusu 2349 usUfsuGfgUfgCfaCfgUfaAfcUfuGfgsusu 2296 CfsasAfgUfuAfcGfuGfcAfcCfaAfaAfsusu 2350 usUfsuUfgGfuGfcAfcGfuAfaCfuUfgsusu 2297 AfsasGfuUfaCfgUfgCfaCfcAfaAfuAfsusu 2351 usAfsuUfuGfgUfgCfaCfgUfaAfcUfususu 2298 GfsusUfaCfgUfgCfaCfcAfaAfuUfaAfsusu 2352 usUfsaAfuUfuGfgUfgCfaCfgUfaAfcsusu 2299 UfsusAfcGfuGfcAfcCfaAfaUfuAfuAfsusu 2353 usAfsuAfaUfuUfgGfuGfcAfcGfuAfasusu 2300 AfsasGfaCfuCfaAfaAfgUfaAfuAfuAfsusu 2354 usAfsuAfuUfaCfuUfuUfgAfgUfcUfususu 2301 AfsasAfaUfcUfaCfuAfaAfaAfgUfcAfsusu 2355 usGfsaCfuUfuUfuAfgUfaGfaUfuUfususu 2302 UfscsUfaCfuAfaAfaAfgUfcUfcUfgAfsusu 2356 usCfsaGfaGfaCfuUfuUfuAfgUfaGfasusu 2303 UfsgsAfaGfaCfgGfgGfcUfaGfaUfaAfsusu 2357 usUfsaUfcUfaGfcCfcCfgUfcUfuCfasusu 2304 CfsusAfgAfuAfuUfgGfgAfgAfaAfcAfsusu 2358 usGfsuUfuCfuCfcCfaAfuAfuCfuAfgsusu 2305 AfsgsCfaGfaAfcGfgUfgAfaAfgUfgAfsusu 2359 usCfsaCfuUfuCfaCfcGfuUfcUfgCfususu 2306 AfsasAfgUfgGfgAfgAfuAfcAfuUfgAfsusu 2360 usCfsaAfuGfuAfuCfuCfcCfaCfuUfususu 2307 AfsasGfuGfgGfaGfaUfaCfaUfuGfgAfsusu 2361 usCfscAfaUfgUfaUfcUfcCfcAfcUfususu 2308 AfsgsUfgGfgAfgAfuAfcAfuUfgGfaAfsusu 2362 usUfscCfaAfuGfuAfuCfuCfcCfaCfususu 2309 UfsgsGfgAfgAfuAfcAfuUfgGfaUfcAfsusu 2363 usGfsaUfcCfaAfuGfuAfuCfuCfcCfasusu 2310 AfsusAfcAfuUfgGfaUfcUfuCfuCfaAfsusu 2364 usUfsgAfgAfaGfaUfcCfaAfuGfuAfususu 2311 CfsasUfuGfgAfuCfuUfcUfcAfuUfgAfsusu 2365 usCfsaAfuGfaGfaAfgAfuCfcAfaUfgsusu 2312 AfsusUfgGfaUfcUfuCfuCfaUfuGfgAfsusu 2366 usCfscAfaUfgAfgAfaGfaUfcCfaAfususu 2313 UfsusGfgAfuCfuUfcUfcAfuUfgGfaAfsusu 2367 usUfscCfaAfuGfaGfaAfgAfuCfcAfasusu 2314 UfsgsGfaUfcUfuCfuCfaUfuGfgAfgAfsusu 2368 usCfsuCfcAfaUfgAfgAfaGfaUfcCfasusu 2315 GfsasUfcUfuCfuCfaUfuGfgAfgAfgAfsusu 2369 usCfsuCfuCfcAfaUfgAfgAfaGfaUfcsusu 2316 UfsusCfuCfaUfuGfgAfgAfgGfaUfaAfsusu 2370 usUfsaUfcCfuCfuCfcAfaUfgAfgAfasusu 2317 CfsusCfaUfuGfgAfgAfgGfaUfaAfaAfsusu 2371 usUfsuUfaUfcCfuCfuCfcAfaUfgAfgsusu 2318 AfsgsAfcAfgUfuAfuGfcGfgAfuUfcAfsusu 2372 usGfsaAfuCfcGfcAfuAfaCfuGfuCfususu 2319 GfsasCfaGfuUfaUfgCfgGfaUfuCfuAfsusu 2373 usAfsgAfaUfcCfgCfaUfaAfcUfgUfcsusu 2320 UfsusAfuGfcGfgAfuUfcUfcUfuGfaAfsusu 2374 usUfscAfaGfaGfaAfuCfcGfcAfuAfasusu 2321 UfsasUfgCfgGfaUfuCfuCfuUfgAfaAfsusu 2375 usUfsuCfaAfgAfgAfaUfcCfgCfaUfasusu 2322 AfsusGfcGfgAfuUfcUfcUfuGfaAfaAfsusu 2376 usUfsuUfcAfaGfaGfaAfuCfcGfcAfususu 2323 UfsasCfaGfaGfuGfgUfgUfuAfcGfgAfsusu 2377 usCfscGfuAfaCfaCfcAfcUfcUfgUfasusu 2324 GfsusGfuUfaCfgGfcGfgUfgGfaAfaAfsusu 2378 usUfsuUfcCfaCfcGfcCfgUfaAfcAfcsusu 2325 UfsgsUfuAfcGfgCfgGfuGfgAfaAfaAfsusu 2379 usUfsuUfuCfcAfcCfgCfcGfuAfaCfasusu 2326 GfsusUfaCfgGfcGfgUfgGfaAfaAfgAfsusu 2380 usCfsuUfuUfcCfaCfcGfcCfgUfaAfcsusu 2327 UfsusAfcGfgCfgGfuGfgAfaAfaGfuAfsusu 2381 usAfscUfuUfuCfcAfcCfgCfcGfuAfasusu 2328 UfsasCfgGfcGfgUfgGfaAfaAfgUfuAfsusu 2382 usAfsaCfuUfuUfcCfaCfcGfcCfgUfasusu 2329 CfsgsGfcGfgUfgGfaAfaAfgUfuUfaAfsusu 2383 usUfsaAfaCfuUfuUfcCfaCfcGfcCfgsusu 2330 AfsgsUfuUfaAfaGfuUfgCfcUfaAfgAfsusu 2384 usCfsuUfaGfgCfaAfcUfuUfaAfaCfususu 2331 UfsusUfaAfaGfuUfgCfcUfaAfgAfaAfsusu 2385 us UfsuCfuUfaGfgCfaAfcUfuUfaAfasusu 2332 UfsgsGfaUfuGfcUfuUfuUfaGfcAfaAfsusu 2386 usUfsuGfcUfaAfaAfaGfcAfaUfcCfasusu 2333 GfsasAfgGfgGfuCfaCfcUfgAfaAfaAfsusu 2387 usUfsuUfuCfaGfgUfgAfcCfcCfuUfcsusu 2334 AfsasAfuAfaAfgUfuCfuCfuUfaGfcAfsusu 2388 usGfscUfaAfgAfgAfaCfuUfuAfuUfususu

TABLE 10 Sequences in siRNA subset H siRNA SEQ ID sense strand  SEQ ID antisense strand  Name NO: sequence (5′-3′) NO: sequence (5′-3′) ETD01220 2389 usgsgcuAfuGfGfcuaguguu 2335 usUfsaAfcAfcUfaGfcCfaUfaGfc aasusu Cfasusu ETD01221 2390 asuscauAfcAfAfacucugua 2336 usGfsuAfcAfgAfgUfuUfgUfaUf casusu gAfususu ETD01222 2391 csusguaCfuuCfCfuggaauc 2337 usCfsgAfuUfcCfaGfgAfaGfuAf gasusu cAfgsusu ETD01223 2392 usgsuaCfuuCfCfuggaaucg 2338 usUfscGfaUfuCfcAfgGfaAfgUf aasusu aCfasusu ETD01224 2393 gsusacUfUfccUfggaaucga 2339 usAfsuCfgAfuUfcCfaGfgAfaGf uasusu uAfcsusu ETD01225 2394 usascuuccuGfGfaaucgauaa 2340 usUfsaUfcGfaUfuCfcAfgGfaAf susu gUfasusu ETD01226 2395 csusuccuGfGfAfAfucgaua 2341 usAfsgUfaUfcGfaUfuCfcAfgGf cuasusu aAfgsusu ETD01227 2396 csusggAfAfucGfAfuacuug 2342 usUfsaCfaAfgUfaUfcGfaUfuCfc uaasusu Afgsusu ETD01228 2397 gsasaucGfAfuAfcuuguauu 2343 usAfsaAfuAfcAfaGfuAfuCfgAf uasusu uUfcsusu ETD01229 2398 csusaguAfccAfAfguuacgu 2344 usCfsaCfgUfaAfcUfuGfgUfaCfu gasusu Afgsusu ETD01230 2399 usasguAfccAfAfguuacgug 2345 usGfscAfcGfuAfaCfuUfgGfuAf casusu cUfasusu ETD01231 2400 asgsuaccAfaGfuuacgugcaa 2346 usUfsgCfaCfgUfaAfcUfuGfgUf susu aCfususu ETD01232 2401 gsusacCfaagUfUfacgugca 2347 usGfsuGfcAfcGfuAfaCfuUfgGf casusu uAfcsusu ETD01233 2402 usasccaagUfUfaCfgugcacc 2348 usGfsgUfgCfaCfgUfaAfcUfuGf asusu gUfasusu ETD01234 2403 cscsaagUfUfaCfgUfgcacc 2349 usUfsuGfgUfgCfaCfgUfaAfcUf aaasusu uGfgsusu ETD01235 2404 csasaguuAfcGfuGfcaccaaa 2350 usUfsuUfgGfuGfcAfcGfuAfaCf asusu uUfgsusu ETD01236 2405 asasguUfaCfgUfgCfaccaa 2351 usAfsuUfuGfgUfgCfaCfgUfaAf auasusu cUfususu ETD01237 2406 gsusuaCfgugCfaCfcaaauu 2352 usUfsaAfuUfuGfgUfgCfaCfgUf aasusu aAfcsusu ETD01238 2407 ususacGfuGfcAfccaaauua 2353 usAfsuAfaUfuUfgGfuGfcAfcGf uasusu uAfasusu ETD01239 2408 asasgacucAfAfAfAfguaau 2354 usAfsuAfuUfaCfuUfuUfgAfgUf auasusu cUfususu ETD01240 2409 asasaaUfCfuaCfUfaaaaagu 2355 usGfsaCfuUfuUfuAfgUfaGfaUf casusu uUfususu ETD01241 2410 uscsuacuAfAfAfAfAfgucu 2356 usCfsaGfaGfaCfuUfuUfuAfgUf cugasusu aGfasusu ETD01242 2411 usgsaaGfacGfGfGfGfcuag 2357 usUfsaUfcUfaGfcCfcCfgUfcUfu auaasusu Cfasusu ETD01243 2412 csusagaUfaUfUfgggagaaa 2358 usGfsuUfuCfuCfcCfaAfuAfuCf casusu uAfgsusu ETD01244 2413 asgscaGfaacGfGfugaaagu 2359 usCfsaCfuUfuCfaCfcGfuUfcUfg gasusu Cfususu ETD01245 2414 asasaguGfggAfgAfuacauu 2360 usCfsaAfuGfuAfuCfuCfcCfaCfu gasusu Ufususu ETD01246 2415 asasguGfgGfaGfauacauug 2361 usCfscAfaUfgUfaUfcUfcCfcAfc gasusu Ufususu ETD01247 2416 asgsugggAfgAfuAfcauugg 2362 usUfscCfaAfuGfuAfuCfuCfcCfa aasusu Cfususu ETD01248 2417 usgsggAfgAfuAfcAfuugg 2363 usGfsaUfcCfaAfuGfuAfuCfuCfc aucasusu Cfasusu ETD01249 2418 asusac AfuuGfGfaucuucuc 2364 usUfsgAfgAfaGfaUfcCfaAfuGf aasusu uAfususu ETD01250 2419 csasuuggaUfCfUfUfcucau 2365 usCfsaAfuGfaGfaAfgAfuCfcAfa ugasusu Ufgsusu ETD01251 2420 asusuggaUfcUfUfcucauug 2366 usCfscAfaUfgAfgAfaGfaUfcCfa gasusu Afususu ETD01252 2421 ususggaUfcUfUfcUfcauug 2367 usUfscCfaAfuGfaGfaAfgAfuCfc gaasusu Afasusu ETD01253 2422 usgsgauCfuuCfuCfauugga 2368 usCfsuCfcAfaUfgAfgAfaGfaUfc gasusu Cfasusu ETD01254 2423 gsasucUfuCfuCfauuggaga 2369 usCfsuCfuCfcAfaUfgAfgAfaGfa gasusu Ufcsusu ETD01255 2424 ususcucAfuuGfGfagaggau 2370 usUfsaUfcCfuCfuCfcAfaUfgAfg aasusu Afasusu ETD01256 2425 csuscauuGfGfAfGfAfggau 2371 usUfsuUfaUfcCfuCfuCfcAfaUfg aaaasusu Afgsusu ETD01257 2426 asgsacAfGfuuAfuGfcggau 2372 usGfsaAfuCfcGfcAfuAfaCfuGf ucasusu uCfususu ETD01258 2427 gsascagUfUfaUfgcggauuc 2373 usAfsgAfaUfcCfgCfaUfaAfcUfg uasusu Ufcsusu ETD01259 2428 ususauGfcGfgAfuucucuug 2374 usUfscAfaGfaGfaAfuCfcGfcAfu aasusu Afasusu ETD01260 2429 usasugCfggaUfUfcucuuga 2375 usUfsuCfaAfgAfgAfaUfcCfgCfa aasusu Ufasusu ETD01261 2430 asusgcggaUfUfcUfcuugaa 2376 usUfsuUfcAfaGfaGfaAfuCfcGfc aasusu Afususu ETD01262 2431 usascaGfaGfuGfGfuguuac 2377 usCfscGfuAfaCfaCfcAfcUfcUfg ggasusu Ufasusu ETD01263 2432 gsusguuacGfGfcGfguggaa 2378 usUfsuUfcCfaCfcGfcCfgUfaAfc aasusu Afcsusu ETD01264 2433 usgsuuaCfggCfgguggaaaa 2379 usUfsuUfuCfcAfcCfgCfcGfuAfa asusu Cfasusu ETD01265 2434 gsusuacGfGfcGfGfuggaaa 2380 usCfsuUfuUfcCfaCfcGfcCfgUfa agasusu Afcsusu ETD01266 2435 ususacGfGfcGfGfuGfgaaa 2381 usAfscUfuUfuCfcAfcCfgCfcGfu aguasusu Afasusu ETD01267 2436 usascggCfggUfggaaaaguu 2382 usAfsaCfuUfuUfcCfaCfcGfcCfg asusu Ufasusu ETD01268 2437 csgsgcGfGfuGfGfaaaaguu 2383 usUfsaAfaCfuUfuUfcCfaCfcGfc uaasusu Cfgsusu ETD01269 2438 asgsuuuAfAfAfGfuugccua 2384 usCfsuUfaGfgCfaAfcUfuUfaAfa agasusu Cfususu ETD01270 2439 ususuaaagUfUfgCfcuaaga 2385 usUfsuCfuUfaGfgCfaAfcUfuUf aasusu aAfasusu ETD01271 2440 usgsgaUfUfgcUfuUfuuagc 2386 usUfsuGfcUfaAfaAfaGfcAfaUfc aaasusu Cfasusu ETD01272 2441 gsasaggggUfCfaCfcugaaa 2387 usUfsuUfuCfaGfgUfgAfcCfcCf aasusu uUfcsusu ETD01273 2334 AfsasAfuAfaAfgUfuCfuC 2388 usGfscUfaAfgAfgAfaCfuUfuAf fuUfaGfcAfsusu uUfususu

Any siRNA among any of subsets A-H may comprise any modification pattern described herein. If a sequence is a different number of nucleotides in length than a modification pattern, the modification pattern may still be used with the appropriate number of additional nucleotides added 5′ or 3′ to match the number of nucleotides in the modification pattern. For example, if a sense or antisense strand of the siRNA among any of subsets A-F comprises 19 nucleotides, and a modification pattern comprises 21 nucleotides, UU may be added onto the 5′ end of the sense or antisense strand.

Chemically modified MTRES1 siRNAs in Table 10 were assayed for MTRES1 mRNA knockdown activity in cells in culture. SK-LMS-1 cells (ATCC® HTB-88) were seeded in 96-well tissue culture plates at a cell density of 7,500 cells per well in EMEM (ATCC Catalog No. 30-2003) supplemented with 10% fetal bovine serum and incubated overnight in a water-jacketed, humidified incubator at 37° C. in an atmosphere composed of air plus 5% carbon dioxide. These siRNAs were derived from sequences in siRNA subset F, and were cross reactive for human and non-human primate. The MTRES1 siRNAs were individually transfected into SK-LMS-1 cells in duplicate wells at 10 nM and 1 nM final concentration using 0.3 μL Lipofectamine RNAiMax (Fisher) per well. Silencer Select Negative Control #1 (ThermoFisher, Catalog #4390843) was transfected at 10 nM and 1 nM final concentration as a control. Silencer Select human MTRES1 (ThermoFisher, Catalog #4427037, ID: s27762) was transfected at 10 nM and 1 nM final concentration and used as a positive control. After incubation for 48 hours at 37° C., total RNA was harvested from each well and cDNA prepared using TaqMan® Fast Advanced Cells-to-CT™ Kit (ThermoFisher, Catalog #A35374) according to the manufacturer's instructions. The level of MTRES1 mRNA from each well was measured in triplicate by real-time qPCR on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan Gene Expression Assay for human MTRES1 (ThermoFisher, assay #Hs00360684_m1). The level of PPIA mRNA was measured using TaqMan Gene Expression Assay (ThermoFisher, assay #Hs99999904_m1) and used to determine relative MTRES1 mRNA levels in each well using the delta-delta Ct method. All data was normalized to relative MTRES1 mRNA levels in untreated SK-LMS-1 cells. The results are shown in Table 11. The siRNAs ETD01228, ETD01270, ETD01251, ETD01235, ETD01249, ETD01258, ETD01268, ETD01273, ETD01263, ETD01240, ETD01223, ETD01262, ETD01239, ETD01242, ETD01272, ETD01220, ETD01261, ETD01243, ETD01269, ETD01256, ETD01241, ETD01238, ETD01247 and ETD01266 reduced MTRES1 levels by greater than 50% when transfected at 10 nM.

TABLE 11 Knockdown Activity of MTRES1-Specific siRNAs at 10 nM and 1 nM in Human SK-LMS-1 Cells Antisense Sense Strand Strand Relative MTRES1 siRNA name SEQ ID NO: SEQ ID NO: mRNA Level Untreated Cells — — 1 10 nM 1 nM siRNA siRNA Negative Control — — 0.93 1.34 siRNA Positive Control — — 0.39 0.8 siRNA ETD01220 2389 2335 0.34 0.87 ETD01221 2390 2336 0.73 1.24 ETD01222 2391 2337 1.03 1.18 ETD01223 2392 2338 0.39 0.57 ETD01224 2393 2339 0.62 0.86 ETD01225 2394 2340 1.13 1.1 ETD01226 2395 2341 0.5 0.69 ETD01227 2396 2342 1.1 1.21 ETD01228 2397 2343 0.5 0.68 ETD01229 2398 2344 0.52 0.96 ETD01230 2399 2345 1.01 1.14 ETD01231 2400 2346 0.52 1 ETD01232 2401 2347 0.78 1.01 ETD01233 2402 2348 0.79 1.11 ETD01234 2403 2349 0.81 0.92 ETD01235 2404 2350 0.44 0.75 ETD01236 2405 2351 0.87 1.04 ETD01237 2406 2352 0.57 0.83 ETD01238 2407 2353 0.28 0.49 ETD01239 2408 2354 0.38 0.76 ETD01240 2409 2355 0.41 0.81 ETD01241 2410 2356 0.29 0.59 ETD01242 2411 2357 0.37 0.61 ETD01243 2412 2358 0.32 0.83 ETD01244 2413 2359 1 1.15 ETD01245 2414 2360 0.98 1.04 ETD01246 2415 2361 0.85 1.05 ETD01247 2416 2362 0.26 0.52 ETD01248 2417 2363 0.92 1.04 ETD01249 2418 2364 0.44 0.78 ETD01250 2419 2365 1.04 1.1 ETD01251 2420 2366 0.47 0.94 ETD01252 2421 2367 0.83 1.17 ETD01253 2422 2368 0.87 1.04 ETD01254 2423 2369 0.92 1.02 ETD01255 2424 2370 0.84 1.03 ETD01256 2425 2371 0.29 0.57 ETD01257 2426 2372 0.75 1 ETD01258 2427 2373 0.44 0.93 ETD01259 2428 2374 0.55 1 ETD01260 2429 2375 0.66 1.33 ETD01261 2430 2376 0.33 0.53 ETD01262 2431 2377 0.39 0.92 ETD01263 2432 2378 0.42 0.76 ETD01264 2433 2379 1 1.28 ETD01265 2434 2380 1 0.94 ETD01266 2435 2381 0.24 0.36 ETD01267 2436 2382 0.9 1.14 ETD01268 2437 2383 0.44 1.06 ETD01269 2438 2384 0.32 0.9 ETD01270 2439 2385 0.5 0.91 ETD01271 2440 2386 0.52 1.15 ETD01272 2441 2387 0.35 0.9 ETD01273 2442 2388 0.44 1.24

The IC50 values for knockdown of MTRES1 mRNA by select MTRES1 siRNAs will be determined in SK-LMS-1 (ATCCR HTB-88) cells. The siRNAs will be assayed individually at 30 nM, 10 nM, 3 nM, 1 nM and 0.3 nM, or 3 nM, 1 nM, 0.3 nM, 0.1 nM and 0.03 nM, or 30 nM, 10 nM, 3 nM, 1 nM, 0.3 nM, 0.1 nM and 0.03 nM. The SK-LMS-1 cells will be seeded in 96-well tissue culture plates at a cell density of 7,500 cells per well in EMEM (ATCC Catalog No. 30-2003) supplemented with 10% fetal bovine serum and incubated overnight in a water-jacketed, humidified incubator at 37° C. in an atmosphere composed of air plus 5% carbon dioxide. The MTRES1 siRNAs will be individually transfected into SK-LMS-1 cells in triplicate wells using 0.3 μL Lipofectamine RNAiMax (Fisher) per well. After incubation for 48 hours at 37° C., total RNA will be harvested from each well and cDNA prepared using TaqMan® Fast Advanced Cells-to-CT™ Kit (ThermoFisher, Catalog #A35374) according to the manufacturer's instructions. The level of MTRES1 mRNA from each well will be measured in triplicate by real-time qPCR on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan Gene Expression Assay for human MTRES1 (ThermoFisher, assay #Hs01568158_m1). The level of PPIA mRNA will be measured using TaqMan Gene Expression Assay (ThermoFisher, assay #Hs99999904_m1) and used to determine relative MTRES1 mRNA levels in each well using the delta-delta Ct method. All data will be normalized to relative MTRES1 mRNA levels in untreated SK-LMS-1 cells. Curve fit will be accomplish using the [inhibitor]vs. response (three parameters) function in GraphPad Prism software.

siRNAs targeted to MTRES1 mRNA that downregulate levels of MTRES1 mRNA may lead to a decrease in mRNA abundance of mitochondrially expressed NADH-ubiquinone oxidoreductase chain 5 protein (ND5), NADH-ubiquinone oxidoreductase chain 6 protein (ND6), cytochrome b (CYTB), and mitochondrially encoded 12S ribosomal RNA (12S rRNA), when administered to the cultured human neuronal cell line HCN-2 under conditions of ethidium bromide induced mitochondrial stress.

On Day 0, HCN-2 cells are to be seeded at 150,000 cells/mL into a Falcon 24-well tissue culture plate (ThermoFisher Cat. No. 353047) at 0.5 mL per well.

On Day 1, cells are treated with ethidium bromide (100 ng/ml), a well-established mitochondrial DNA replication/transcription inhibitor and stressor. Also on Day 1, MTRES1 siRNA and negative control siRNA master mixes are prepared. The MTRES1 siRNA master mix contains 350 μL of Opti-MEM (ThermoFisher Cat. No. 4427037-s1288 Lot No. AS02B02D) and 3.5 μL of a mixture of two MTRES1 siRNAs (10 μM stock). The negative control siRNA master mix contains 350 μL of Opti-MEM and 3.5 μL of negative control siRNA (ThermoFisher Cat. No. 4390843, 10 μM stock). Next, 3 μL of TransIT-X2 (Mirus Cat. No. MIR-6000) is added to each master mix. The mixes are incubated for 15 minutes to allow transfection complexes to form, then 51 μL of the appropriate master mix+TransIT-X2 is added to duplicate wells of HCN-2 cells with a final siRNA concentration of 10 nM.

On Day 3, 48 hours post transfection, duplicate wells are lysed using the Cells-to-Ct kit according to the manufacturer's protocol (ThermoFisher Cat. No. 4399002) or protein lysis buffer containing protease and phosphatase inhibitors. For the Cells-to-Ct, cells are washed with 50 μL using cold 1×PBS and lysed by adding 49.5 μL of Lysis Solution and 0.5 μL DNase I per well and pipetting up and down 5 times and incubating for 5 minutes at room temperature. Stop Solution (5 μL/well) is added to each well and mixed by pipetting up and down five times and incubating at room temperature for 2 minutes. The reverse transcriptase reaction is performed using 22.5 μL of the lysate according to the manufacturer's protocol. Samples are stored at −80° C. until real-time qPCR is performed in triplicate using TaqMan Gene Expression Assays (Applied Biosystems FAM/MTRES1, FAM/ND5, FAM/ND6, FAM/CYTB and FAM/12srRNA and using a BioRad CFX96 Cat. No. 1855195).

A decrease in MTRES1 mRNA expression in the HCN-2 cells is expected after transfection with the MTRES1 siRNAs compared to MTRES1 mRNA levels in HCN-2 cells transfected with the non-specific control siRNA 48 hours after transfection. There is an expected decrease in abundance of mitochondrial expressed genes ND5, ND6, CYTB and 12s rRNA mRNA. These results will show that the MTRES1 siRNAs elicit knockdown of MTRES1 mRNA in HCN-2 cells, and that the decrease in MTRES1 expression is correlated with a decrease in abundance of mitochondrial expressed genes ND5, ND6, CYTB and 12s rRNA mRNA.

ASOs targeted to MTRES1 mRNA that downregulate levels of MTRES1 mRNA may lead to a decrease in mRNA abundance of mitochondrial expressed ND5, ND6, CYTB and 12s rRNA, when administered to the cultured human neuronal cell line HCN-2 under conditions of ethidium bromide induced mitochondrial stress.

On Day 0, HCN-2 cells are to be seeded at 150,000 cells/mL into a Falcon 24-well tissue culture plate (ThermoFisher Cat. No. 353047) at 0.5 mL per well.

On Day 1, cells are treated with ethidium bromide (100 ng/ml), a well-established mitochondrial DNA replication/transcription inhibitor and stressor. Also on Day 1, MTRES1 ASO and negative control ASO master mixes are prepared. The MTRES1 ASO master mix contains 350 μL of Opti-MEM (ThermoFisher Cat. No. 4427037-s1288 Lot No. AS02B02D) and 3.5 μL of a mixture of two MTRES1 ASOs (10 μM stock). The negative control ASO master mix contains 350 μL of Opti-MEM and 3.5 μL of negative control ASO (ThermoFisher Cat. No. 4390843, 10 μM stock). Next, 3 μL of TransIT-X2 (Mirus Cat. No. MIR-6000) is added to each master mix. The mixes are incubated for 15 minutes to allow transfection complexes to form, then 51 μL of the appropriate master mix+TransIT-X2 is added to duplicate wells of HCN-2 cells with a final ASO concentration of 10 nM.

On Day 3, 48 hours post transfection, duplicate wells are lysed using the Cells-to-Ct kit according to the manufacturer's protocol (ThermoFisher Cat. No. 4399002) or protein lysis buffer containing protease and phosphatase inhibitors. For the Cells-to-Ct, cells are washed with 50 μL using cold 1×PBS and lysed by adding 49.5 μL of Lysis Solution and 0.5 μL DNase I per well and pipetting up and down 5 times and incubating for 5 minutes at room temperature. Stop Solution (5 μL/well) is added to each well and mixed by pipetting up and down five times and incubating at room temperature for 2 minutes. The reverse transcriptase reaction is performed using 22.5 μL of the lysate according to the manufacturer's protocol. Samples are stored at −80° C. until real-time qPCR is performed in triplicate using TaqMan Gene Expression Assays (Applied Biosystems FAM/MTRES1, FAM/ND5, FAM/ND6, FAM/CYTB and FAM/12srRNA and using a BioRad CFX96 Cat. No. 1855195).

A decrease in MTRES1 mRNA expression in the HCN-2 cells is expected after transfection with the MTRES1 ASOs compared to MTRES1 mRNA levels in HCN-2 cells transfected with the non-specific control ASO 48 hours after transfection. There is an expected decrease in abundance of mitochondrial expressed genes ND5, ND6, CYTB and 12s rRNA mRNA. These results will show that the MTRES1 ASOs elicit knockdown of MTRES1 mRNA in HCN-2 cells, and that the decrease in MTRES1 expression is correlated with a decrease in abundance of mitochondrial expressed genes ND5, ND6, CYTB and 12s rRNA mRNA.

In this experiment, a mouse model of Alzheimer's Disease (AD) will be used to evaluate effects of the siRNAs described herein that target MTRES1. In some embodiments, the siRNA comprises one or more of SEQ ID NOS: 2675, 2677-2686, 2689, 2720, 2729, 2739, 2745, 2748, 2749, 2754, 2758-2762, 2766, 2767, 2769, 2770, 2786, 2787-2812, 2814-2816, 2819-2822, 2824, 2828-2833, 2836, 2838, 2839, 2857, 2859-2868, 2871, 2873, 2874, 2877-2879, 2940-2944, 2948-2952, 2968-2994, 2996-2998, 3001-3004, 3006, 3010, 3011, 3013-3015, 3018, and 3020. The model includes 5×FAD (Tg6799) mice which express human amyloid beta precursor protein (APP) and presenilin-1 (PSEN1) transgenes with five AD-linked mutations. Cognitive function is measured using a Barnes maze (BM) test and novel object recognition test (NORT).

Three-month-old mice are divided into two groups: Group 1—a group treated with the siRNA targeting MTRES1, Group 2—a group treated with vehicle.

−1 Mice are administered the siRNA or the vehicle by intracerebroventricular injection on day 0 of treatment. Mice are induced to anesthetic states in an induction chamber with 1.2% isoflurane vaporized by oxygen of 1.0 L/min and then transferred and fixed to a stereotaxic frame while keeping anesthetized by 0.8% isoflurane through a mask. The skulls are exposed and single intracerebroventricular injections (5 μL, artificial cerebrospinal fluid as vehicle) are performed at 500 nL minafter needle placement at the following coordinates from bregma: −0.2 mm anterior-posterior, 0.8 mm mediolateral and −2.5 mm dorsoventral using a Standard U-Frame Stereotaxic Instrument for Mouse (Harvard Apparatus 75-1808) and a Stereotaxic Anesthesia Adapters with Anesthesia Masks (Harvard Apparatus 75-1856). Dosing for each group will be repeated on day 180 of treatment following the same procedures.

The behavioral tests are performed on day 180 and day 360 of treatment, when the mice are 9 and 15 months old, respectively. To rule out nonspecific motor effects that could influence the results, the potential effect of treatment on locomotor activity is assessed. Mice are evaluated using the openfield apparatus (40×40×30 cm) in a sound-attenuated room. The total distance (cm) traveled by each mouse is recorded for 5 min by a video tracking system (ANY-maze; Stoelting Co., Wood Dale, IL) and is used to quantify activity levels. The floor of the open-field apparatus is cleaned with 70% ethanol between tests.

The novel object recognition test based on the spontaneous tendency of rodents to spend more time exploring a novel object than a familiar one. Exploration of the novel object reflects the use of learning and recognition memory. On the first day of testing, animals are first placed in a novel object apparatus (40×40×30 cm) and allowed to explore two identical objects for a period of 5 mins. Time spent investigating each object is recorded by video tracking system. After a 24 hr. interval, the animal is returned to the novel object apparatus, which contains the familiar object and a novel object and allowed to explore for 5-mins and time spent investigating each object is recorded by video tracking system. Object recognition in cognitively intact animals is distinguished by more time spent interacting with the novel object and calculated as [(novel object investigation time)/(total investigation time of both objects)*100]. This metric can be used to compare memory retention of treated versus control animals.

The Barnes maze is behavioral test useful for screening potential drugs that influence cognition and assessing other manipulations that are expected to affect cognitive related behaviors. The task measures these parameters by observing the ability of the subject to remember the location of the target hole leading to an enclosed escape chamber. The testing maze is constructed of matte white Plexiglas circle (92 cm diameter) with 20 holes equally spaced around the perimeter (5 cm hole diameter) at a height of 95 cm. During the habituation trail (Day 1:3 mins.), the animal is initially placed in the center of the maze under a starting cup or covered area. After a predetermined period, the cup is lifted, and the animal is allowed to explore the maze and find the escape box. The animal's speed, path length, latency to find the escape box and number of errors (visiting incorrect holes) is recorded (ANY-maze; Stoelting Co., Wood Dale, IL). The acquisition phase consists of four sessions per day for four consecutive days (Days 2-4) with an inter-trial-interval of 20 mins. During each session, the animal's speed, path length, latency to find the escape box and number of errors (visiting incorrect holes) is recorded (ANY-maze; Stoelting Co., Wood Dale, IL). With continued trials, shorter latencies, and path distance to reach an escape box are expected because in order to resolve the maze. 24 hrs. after the final acquisition trial, a 2 min. probe trial is performed where the target hole is closed, and the time spend on the vicinity of the previously correct hole (or the correct zone) is measured.

Twenty-four hours after behavioral assessment, all animals will be anesthetized with isoflurane to effect and CSF will be collected (followed by thoracotomy), and the samples will be centrifuged for 10 min at +4° C. and transferred to a sterile tubes. CSF will be snap frozen in liquid nitrogen. Following CSF collection blood will be collected and processed to serum. Brains and spinal cord are removed, and brain hemispheres separated along the midline. Brain halves are either flash frozen and stored at −80° C. until processing for subsequent biochemical analysis or drop-fixed in 10% neutral-buffered formalin.

Amyloid burden is assessed using 5-nm-thick sections from Formalin fixed paraffin embedded (FFPE) tissue are deparaffinized with xylene and rehydrated using a gradient of alcohol. Next, heat-induced antigen retrieval is carried out on sections. Sections are blocked at room temperature (RT) before primary antibodies (AB) are diluted and incubated overnight at RT in a humid chamber. Secondary antibody treatment is performed by incubation with fluorescent-labeled antibodies. Amyloid burden is acquired by measuring the total number of Aβ plaques and their size, expressed in area units (nm2) in the brain area analyzed in an individual section. The immunopositive signal (AB plaques) within the selected brain region is identified by a threshold level mask, which is maintained throughout the whole analysis per timeframe for uniformity. Then, the total number of amyloid plaques and their area is obtained.

For measurement of neurofilament-light (NF-L) levels in terminal serum samples, the NF-Light Serum ELISA (UmanDiagnostics) is used without modifications. Samples are diluted 1:2.5-1:10 in assay buffer and analyzed using 50 μl per sample according to the manufacturer's protocol.

Measurements of AB42 and AB40 concentrations in serum and tissue extracts is measured using the MILLIPLEX® MAP Mouse Amyloid Beta Magnetic Bead Panel (Millipore) without modifications according to manufacturer's protocol. Data is acquired and analyzed on a Luminex instrument according to specifications outlined by the manufacturer.

Total RNA is extracted from homogenized tissue and reverse transcribed to cDNA using a First-Strand III cDNA Synthesis kit. Normalized cDNA quantification is carried out by real-time TaqMan PCR using fluorescently labeled TaqMan assays for mouse MTRES1 (ThermoFisher, assay #Mm01229834_m1) and the mouse housekeeping gene PPIA (ThermoFisher, assay #Mm02342430_g1) . . . . Reactions are carried out in 20 μL aliquots using TaqMan Universal PCR Master Mix No AmpErase UNG ran on an ABI Prism 7500 Fast Real-Time PCR System Sequence Detection System and analyzed by the 7500 System software. Relative Quantification (RQ) values between treated and untreated samples are calculated by the formula 2-AACT, where CT is the cycle at threshold (automatic measurement), ΔCT is CT of the assayed gene (MTRES1) minus CT of the endogenous control (PPIA), and AACT is the ΔCT of the normalized assayed gene in the treated sample minus the ΔCT of the same gene in the untreated one (calibrator).

A decrease in MTRES1 mRNA expression in the brain and spinal cord tissues from mice dosed with the MTRES1 siRNA is expected compared to MTRES1 mRNA levels in the brain and spinal cord tissues from mice dosed with vehicle. Shorter latencies, and path distance to reach an escape box are expected in the Barnes maze test in mice that receive the MTRES1 siRNA compared to mice that receive vehicle. Compared to mice that receive vehicle, mice that receive MTRES1 siRNA are expected to more time spent interacting with the novel object in the novel object recognition test. No change is expected between treatment groups in the locomotor activity test. These results will show that the MTRES1 siRNAs elicit knockdown of MTRES1 mRNA in brain and spinal cord tissues, and that the decrease in MTRES1 expression is correlated with better performance in behavioral assessments that measure cognitive function as well as decreased amyloid burden and Aβ pathology. Neurofilament-light (NF-L) concentration in serum is increased and associated with disease progression in the 5×FAD mice receiving vehicle, but mice treated with MTRES1 siRNA are expected to have lower NF-L levels in comparison. These results will indicate that administration of an siRNA targeting MTRES1 to a mammalian subject may be used to treat neurological disorder that includes cognitive decline.

Several siRNAs designed to be cross-reactive with human and mouse MTRES1 mRNA were tested for activity in mice. The siRNAs were attached to the GalNAc ligand ETL1. The siRNA sequences are shown in Table 12A, where Nf is a 2′-fluoro-modified nucleoside, n is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate linkage.

Six- to eight-week-old female mice (strain ICR, n=3) were given a subcutaneous injection on Day 0 of a single 200 μg dose of a GalNAc-conjugated siRNA or PBS as vehicle control.

Mice were euthanized on Day 14 after injection and a liver sample from each was collected and placed in RNAlater (ThermoFisher Catalog #AM7020) until processing. Total liver RNA was prepared by homogenizing the liver tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer's recommendations. Preparation of cDNA was performed using Quanta qScript cDNA SuperMix (VWR, Catalog #95048-500) according to the manufacturer's instructions. The relative levels of liver MTRES1 mRNA were assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for mouse MTRES1 (ThermoFisher, assay #Mm01229834_m1) and the mouse housekeeping gene PPIA (ThermoFisher, assay #Mm02342430_g1) and PerfeCTa® qPCR FastMix®, Low ROX™ (VWR, Catalog #101419-222). Data were normalized to the mean MTRES1 mRNA level in animals receiving PBS. Results are shown in Table 13. Mice injected with ETD01506, ETD01507, ETD01508, and ETD01509 had substantially lower levels in mean liver MTRES1 mRNA on Day 14 relative to mice receiving PBS.

TABLE 12A Description of Example siRNAs with Sequences Sense Antisense Strand Strand siRNA SEQ ID Sense Strand Sequence  SEQ ID Antisense Strand  Name NO: (5′-3′) with GalNAc moiety NO: Sequence (5′-3′) ETD01506 2463 [ETL1]UfscsgaUfaCfuUfgUfaUf 2467 usGfsaAfaAfaUfaCfaAfgUfaUf uUfuUfcasusu cGfasusu ETD01507 2464 [ETL1]csusAfcAfaAfgGfuGfaA 2468 usCfsugaGfuUfcaccuUfuGfuag fcucAfgAfsusu susu ETD01508 2465 [ETL1]AfsusGfgAfaGfaAfaAfg 2469 usGfsuucUfgCfuuuucUfuCfcau caGfaAfcAfsusu susu ETD01509 2466 [ETL1]csusuucuAfcAfaAfgGfu 2470 usGfsuUfcAfcCfuUfuGfuAfgA GfaAfcAfsusu faAfgsusu

TABLE 12B Example siRNA Base Sequences SEQ Sense Strand Base  SEQ siRNA ID Sequence (5′ to 3′) ID Antisense Strand Base Name NO: NO: Sequence (5′ to 3′) ETD01506 2550 UCGAUACUUGUAUUUUUCAUU 2612 UGAAAAAUACAAGUAUCGAUU ETD01507 2551 CUACAAAGGUGAACUCAGAUU 2613 UCUGAGUUCACCUUUGUAGUU ETD01508 2552 AUGGAAGAAAAGCAGAACAUU 2614 UGUUCUGCUUUUCUUCCAUUU ETD01509 2553 CUUUCUACAAAGGUGAACAUU 2615 UGUUCACCUUUGUAGAAAGUU SEQ Sense Strand Base SEQ Antisense Strand Base siRNA ID Sequence (5′ to 3′), ID Sequence (5′ to 3′), Name NO: without 3′ overhangs NO: without 3′ overhangs ETD01506 2554 UCGAUACUUGUAUUUUUCA 2616 UGAAAAAUACAAGUAUCGA ETD01507 2555 CUACAAAGGUGAACUCAGA 2617 UCUGAGUUCACCUUUGUAG ETD01508 2556 AUGGAAGAAAAGCAGAACA 2618 UGUUCUGCUUUUCUUCCAU ETD01509 2557 CUUUCUACAAAGGUGAACA 2619 UGUUCACCUUUGUAGAAAG

TABLE 13 Relative MTRES1 mRNA Levels in Livers of Mice Dose Mean MTRES1 mRNA (Normalized Group n Treatment (ug) to Group 1, Day 14) 1 3 PBS 0 1 2 3 ETD01506 200 0.27 3 3 ETD01507 200 0 4 3 ETD01508 200 0.51 5 3 ETD01509 200 0.51

Several siRNAs designed to be cross-reactive with human and cynomolgus monkey MTRES1 mRNA were tested for activity in mice following transfection with an adeno-associated viral vector. The siRNAs were attached to the GalNAc ligand ETL17. The siRNA sequences are shown in Table 14A, where “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, “d” is a deoxynucleoside, and “s” is a phosphorothioate linkage.

Six- to eight-week-old female mice (C57Bl/6) were injected with 10 μL of a recombinant adeno-associated virus 8 (AAV8) vector (8.8×10E12 genome copies/mL) by the retroorbital route on Day-13. The recombinant AAV8 contained the open reading frame and the majority of the 3′UTR of the human MTRES1 sequence (NM_016487.5) under the control of the human thyroxine binding globulin promoter in an AAV2 backbone packaged in AAV8 capsid (AAV8-TBG-h-MTRES1). On Day 0, infected mice (n=4) were given a subcutaneous injection of a single 100 μg dose of a GalNAc-conjugated siRNA or PBS as vehicle control.

Mice were euthanized on Day 10 after subcutaneous injection and a liver sample from each was collected and placed in RNAlater (ThermoFisher Catalog #AM7020) until processing. Total liver RNA was prepared by homogenizing the liver tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer's recommendations. Preparation of cDNA was performed using Quanta qScript cDNA SuperMix (VWR, Catalog #95048-500) according to the manufacturer's instructions. The relative levels of liver MTRES1 mRNA were assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for human MTRES1 (ThermoFisher, assay #Hs01568158_g1) and the mouse housekeeping gene PPIA (ThermoFisher, assay #Mm02342430_g1) and PerfeCTa® qPCR FastMix®, Low ROX™ (VWR, Catalog #101419-222). Data were normalized to the mean MTRES1 mRNA level in animals receiving PBS. Results are shown in Table 15. Mice injected with ETD01880, 1886, 1887, 1888, 1893 had greatest reductions in mean liver MTRES1 mRNA on Day 10 relative to mice receiving PBS.

TABLE 14A Example siRNA Sequences Anti- Sense sense Strand Sense Strand  Strand siRNA SEQ ID Sequence (5′-3′) SEQ Antisense Strand  Name NO: with GalNAc moiety ID NO: Sequence (5′-3′) ETD01879 2471 [ETL17]suacaaaCfUfCfU 2488 usGfsgAfaGfuAfcAfgAfg fguacuuccasusu UfuUfgUfasusu ETD01880 2472 [ETL17]suguaCfUfUfCfC 2489 usUfscGfaUfuCfcAfgGfa fuggaaucgaasusu AfgUfaCfasusu ETD01881 2473 [ETL17]suacuUfcCfUfdG 2490 usUfsaUfcGfaUfuCfcAfg gaaucgauaasusu GfaAfgUfasusu ETD01882 2474 [ETL17]sgaaucGfAfuAfc 2491 usAfsaAfuAfcAfaGfuAfu uuguauuuasusu CfgAfuUfcsusu ETD01883 2475 [ETL17]suucuagUfaCfCf 2492 usCfsgUfaAfcUfuGfgUfa aaguuacgasusu CfuAfgAfasusu ETD01884 2476 [ETL17]saguuAfcGfuGfc 2493 usAfsaUfuUfgGfuGfcAfc Afccaaauuasusu GfuAfaCfususu ETD01885 2477 [ETL17]suuacGfuGfcAfc 2494 usAfsuAfaUfuUfgGfuGfc caaauuauasusu AfcGfuAfasusu ETD01886 2478 [ETL17]saaaaUfCfuaCfU 2495 usGfsaCfuUfuUfuAfgUfa faaaaagucasusu GfaUfuUfususu ETD01887 2479 [ETL17]saucuAfcuAfAfA 2496 usAfsgAfgAfcUfuUfuUfa fAfagucucuasusu GfuAfgAfususu ETD01888 2480 [ETL17]scuagaUfaUfUfg 2497 usGfsuUfuCfuCfcCfaAfu ggagaaacasusu AfuCfuAfgsusu ETD01889 2481 [ETL17]scauuggaUfCfUf 2498 usCfsaAfuGfaGfaAfgAfu Ufcucauugasusu CfcAfaUfgsusu ETD01890 2482 [ETL17]suuggaUfCfUfUf 2499 usUfscCfaAfuGfaGfaAfg Cfucauuggaasusu AfuCfcAfasusu ETD01891 2483 [ETL17]sauacAfgAfGfdT 2500 usCfsgUfaAfcAfcCfaCfu gguguuacgasusu CfuGfuAfususu ETD01892 2484 [ETL17]saguuuAfAfAfGf 2501 usCfsuUfaGfgCfaAfcUfu uugccuaagasusu UfaAfaCfususu ETD01893 2485 [ETL17]suuuaaagUfUfgC 2502 usUfsuCfuUfaGfgCfaAfc fcuaagaaasusu UfuUfaAfasusu ETD01894 2486 [ETL17]suggaUfUfgCfUf 2503 usUfsuGfcUfaAfaAfaGfc uUfuuagcaaasusu AfaUfcCfasusu ETD01895 2487 [ETL17]saaauAfaAfGfdT 2504 usGfscUfaAfgAfgAfaCfu ucucuuagcasusu UfuAfuUfususu

TABLE 14B Example siRNA Base Sequences siRNA SEQ ID Sense Strand Base SEQ ID Antisense Strand Base Name NO: Sequence (5′ to 3′) NO: Sequence (5′ to 3′) ETD01879 2558 UACAAACUCUGUACUUCCAUU 2620 UGGAAGUACAGAGUUUGUAUU ETD01880 2559 UGUACUUCCUGGAAUCGAAUU 2621 UUCGAUUCCAGGAAGUACAUU ETD01881 2560 UACUUCCUGGAAUCGAUAAUU 2622 UUAUCGAUUCCAGGAAGUAUU ETD01882 2561 GAAUCGAUACUUGUAUUUAUU 2623 UAAAUACAAGUAUCGAUUCUU ETD01883 2562 UUCUAGUACCAAGUUACGAUU 2624 UCGUAACUUGGUACUAGAAUU ETD01884 2563 AGUUACGUGCACCAAAUUAUU 2625 UAAUUUGGUGCACGUAACUUU ETD01885 2564 UUACGUGCACCAAAUUAUAUU 2626 UAUAAUUUGGUGCACGUAAUU ETD01886 2565 AAAAUCUACUAAAAAGUCAUU 2627 UGACUUUUUAGUAGAUUUUUU ETD01887 2566 AUCUACUAAAAAGUCUCUAUU 2628 UAGAGACUUUUUAGUAGAUUU ETD01888 2567 CUAGAUAUUGGGAGAAACAUU 2629 UGUUUCUCCCAAUAUCUAGUU ETD01889 2568 CAUUGGAUCUUCUCAUUGAUU 2630 UCAAUGAGAAGAUCCAAUGUU ETD01890 2569 UUGGAUCUUCUCAUUGGAAUU 2631 UUCCAAUGAGAAGAUCCAAUU ETD01891 2570 AUACAGAGTGGUGUUACGAUU 2632 UCGUAACACCACUCUGUAUUU ETD01892 2571 AGUUUAAAGUUGCCUAAGAUU 2633 UCUUAGGCAACUUUAAACUUU ETD01893 2572 UUUAAAGUUGCCUAAGAAAUU 2634 UUUCUUAGGCAACUUUAAAUU ETD01894 2573 UGGAUUGCUUUUUAGCAAAUU 2635 UUUGCUAAAAAGCAAUCCAUU ETD01895 2574 AAAUAAAGTUCUCUUAGCAUU 2636 UGCUAAGAGAACUUUAUUUUU Sense Strand Base  Antisense Strand Base siRNA SEQ ID Sequence (5′ to 3′), SEQ ID Sequence (5′ to 3′), Name NO: without 3′ overhangs NO: without 3′ overhangs ETD01879 2575 UACAAACUCUGUACUUCCA 2637 UGGAAGUACAGAGUUUGUA ETD01880 2576 UGUACUUCCUGGAAUCGAA 2638 UUCGAUUCCAGGAAGUACA ETD01881 2577 UACUUCCUGGAAUCGAUAA 2639 UUAUCGAUUCCAGGAAGUA ETD01882 2578 GAAUCGAUACUUGUAUUUA 2640 UAAAUACAAGUAUCGAUUC ETD01883 2579 UUCUAGUACCAAGUUACGA 2641 UCGUAACUUGGUACUAGAA ETD01884 2580 AGUUACGUGCACCAAAUUA 2642 UAAUUUGGUGCACGUAACU ETD01885 2581 UUACGUGCACCAAAUUAUA 2643 UAUAAUUUGGUGCACGUAA ETD01886 2582 AAAAUCUACUAAAAAGUCA 2644 UGACUUUUUAGUAGAUUUU ETD01887 2583 AUCUACUAAAAAGUCUCUA 2645 UAGAGACUUUUUAGUAGAU ETD01888 2584 CUAGAUAUUGGGAGAAACA 2646 UGUUUCUCCCAAUAUCUAG ETD01889 2585 CAUUGGAUCUUCUCAUUGA 2647 UCAAUGAGAAGAUCCAAUG ETD01890 2586 UUGGAUCUUCUCAUUGGAA 2648 UUCCAAUGAGAAGAUCCAA ETD01891 2587 AUACAGAGTGGUGUUACGA 2649 UCGUAACACCACUCUGUAU ETD01892 2588 AGUUUAAAGUUGCCUAAGA 2650 UCUUAGGCAACUUUAAACU ETD01893 2589 UUUAAAGUUGCCUAAGAAA 2651 UUUCUUAGGCAACUUUAAA ETD01894 2590 UGGAUUGCUUUUUAGCAAA 2652 UUUGCUAAAAAGCAAUCCA ETD01895 2591 AAAUAAAGTUCUCUUAGCA 2653 UGCUAAGAGAACUUUAUUU

TABLE 15 Relative human MTRES1 mRNA Levels in Livers of Mice Dose Mean MTRES1 mRNA (Normalized Group n Treatment (ug) to Group 1, Day 10) 1 4 PBS 0 1 2 4 ETD01879 100 0.7 3 4 ETD01880 100 0.45 4 4 ETD01881 100 0.78 5 4 ETD01882 100 2.07 6 4 ETD01883 100 1.24 7 4 ETD01884 100 1.12 8 4 ETD01885 100 0.97 9 4 ETD01886 100 0.46 10 4 ETD01887 100 0.18 11 4 ETD01888 100 0.14 12 4 ETD01889 100 0.74 13 4 ETD01890 100 1.73 14 4 ETD01891 100 3.21 15 4 ETD01892 100 2.59 16 4 ETD01893 100 0.55 17 4 ETD01894 100 1.12 18 4 ETD01895 100 0.65

Several siRNAs designed to be cross-reactive with human, mouse and cynomolgus monkey MTRES1 mRNA were tested for activity in mice. The siRNAs were attached to the GalNAc ligand ETL1 or ETL17. The siRNA sequences are shown in Table 16A, where Nf is a 2′-fluoro-modified nucleoside, n is a 2′-O-methyl modified nucleoside, “d” is a deoxynucleoside, and “s” is a phosphorothioate linkage.

Six- to eight-week-old female mice (strain ICR, n=3) were given a subcutaneous injection on Day 0 of a single 200 μg dose of a GalNAc-conjugated siRNA or PBS as vehicle control.

Mice were euthanized on Day 10 after injection and a liver sample from each was collected and placed in RNAlater (ThermoFisher Catalog #AM7020) until processing. Total liver RNA was prepared by homogenizing the liver tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer's recommendations. Preparation of cDNA was performed using Quanta qScript cDNA SuperMix (VWR, Catalog #95048-500) according to the manufacturer's instructions. The relative levels of liver MTRES1 mRNA were assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for mouse MTRES1 (ThermoFisher, assay #Mm01229834_m1) and the mouse housekeeping gene PPIA (ThermoFisher, assay #Mm02342430_g1) and PerfeCTa® qPCR FastMix®, Low ROX™ (VWR, Catalog #101419-222). Data were normalized to the mean MTRES1 mRNA level in animals receiving PBS. Results are shown in

TABLE 17 Mice injected with ETD01597, ETD01955, ETD01958, and had substantially lower levels in mean liver MTRESI mRNA on Day 10 relative to mice receiving PBS. Table 16A. Example siRNA Sequences Sense Antisense Strand Sense Strand  Strand siRNA SEQ ID Sequence (5′-3′)  SEQ Antisense Strand  Name NO: with GalNAc moiety ID NO: Sequence (5′-3′) ETD01597 2505 [ETL1]sguaucuccAfgAfaug 2515 usAfsuAfaCfaUfuCfuGfgAf uuauasusu gAfuAfcsusu ETD01954 2506 [ETL17] sacuuccuGfGfAfA 2516 usGfsuAfsuCfgAfuUfcCfaG fucgauacasusu fgAfaGfususu ETD01955 2507 [ETL17] scuuccuGfGfAfAf 2517 usAfsgUfaUfcGfaUfuCfcAf ucgauacuasusu gGfaAfgsusu ETD01956 2508 [ETL17]scuggAfAfucGfAf 2518 usUfsaCfaAfgUfaUfcGfaUf uacuuguaasusu uCfcAfgsusu ETD01957 2509 [ETL17]sggaa UfCfgaUfaCf 2519 usAfsaUfaCfaAfgUfaUfcGf uuguauuasusu aUfuCfcsusu ETD01958 2510 [ETL17] sgaugCfUfuUfCfu 2520 usAfscCfuUfuGfuAfgAfaAf acaaagguasusu gCfaUfcsusu ETD01959 2511 [ETL17]sagaaAfAfgcAfGf 2521 usUfscAfcCfgUfuCfuGfcUf aacggugaasusu uUfuCfususu ETD01960 2512 [ETL17] saagcagAfAfdCGf 2522 usAfscUfuUfcAfcCfgUfuCf gugaaaguasusu uGfcUfususu ETD01961 2513 [ETL17] sagugGfGfaGfAfu 2523 usUfscCfaAfuGfuAfuCfuCf Afcauuggaasusu cCfaCfususu ETD01962 2514 [ETL17]suggg AfGfauAfcA 2524 usGfsaUfcCfaAfuGfuAfuCf fuuggaucasusu uCfcCfasusu

TABLE 16B Example siRNA Base Sequences SEQ SEQ siRNA ID Sense Strand Base  ID Antisense Strand Base Name NO: Sequence (5′ to 3′) NO: Sequence (5′ to 3′) ETD01597 2592 GUAUCUCCAGAAUGUUAUAUU 2654 UAUAACAUUCUGGAGAUACUU ETD01954 2593 ACUUCCUGGAAUCGAUACAUU 2655 UGUAUCGAUUCCAGGAAGUUU ETD01955 2594 CUUCCUGGAAUCGAUACUAUU 2656 UAGUAUCGAUUCCAGGAAGUU ETD01956 2595 CUGGAAUCGAUACUUGUAAUU 2657 UUACAAGUAUCGAUUCCAGUU ETD01957 2596 GGAAUCGAUACUUGUAUUAUU 2658 UAAUACAAGUAUCGAUUCCUU ETD01958 2597 GAUGCUUUCUACAAAGGUAUU 2659 UACCUUUGUAGAAAGCAUCUU ETD01959 2598 AGAAAAGCAGAACGGUGAAUU 2660 UUCACCGUUCUGCUUUUCUUU ETD01960 2599 AAGCAGAACGGUGAAAGUAUU 2661 UACUUUCACCGUUCUGCUUUU ETD01961 2600 AGUGGGAGAUACAUUGGAAUU 2662 UUCCAAUGUAUCUCCCACUUU ETD01962 2601 UGGGAGAUACAUUGGAUCAUU 2663 UGAUCCAAUGUAUCUCCCAUU SEQ Sense Strand Base  SEQ Antisense Strand Base siRNA ID Sequence (5′ to 3′),  ID Sequence (5′ to 3′), Name NO: without 3′ overhangs NO: without 3′ overhangs ETD01597 2602 GUAUCUCCAGAAUGUUAUA 2664 UAUAACAUUCUGGAGAUAC ETD01954 2603 ACUUCCUGGAAUCGAUACA 2665 UGUAUCGAUUCCAGGAAGU ETD01955 2604 CUUCCUGGAAUCGAUACUA 2666 UAGUAUCGAUUCCAGGAAG ETD01956 2605 CUGGAAUCGAUACUUGUAA 2667 UUACAAGUAUCGAUUCCAG ETD01957 2606 GGAAUCGAUACUUGUAUUA 2668 UAAUACAAGUAUCGAUUCC ETD01958 2607 GAUGCUUUCUACAAAGGUA 2669 UACCUUUGUAGAAAGCAUC ETD01959 2608 AGAAAAGCAGAACGGUGAA 2670 UUCACCGUUCUGCUUUUCU ETD01960 2609 AAGCAGAACGGUGAAAGUA 2671 UACUUUCACCGUUCUGCUU ETD01961 2610 AGUGGGAGAUACAUUGGAA 2672 UUCCAAUGUAUCUCCCACU ETD01962 2611 UGGGAGAUACAUUGGAUCA 2673 UGAUCCAAUGUAUCUCCCA

TABLE 17 Relative MTRES1 mRNA Levels in Livers of Mice Dose Mean MTRES1 mRNA (Normalized Group n Treatment (ug) to Group 1, Day 10) 1 3 PBS 1 2 3 ETD01597 200 0.13 3 3 ETD01954 200 1.03 4 3 ETD01955 200 0.16 5 3 ETD01956 200 0.62 6 3 ETD01957 200 0.31 7 3 ETD01958 200 0.18 8 3 ETD01959 200 0.53 9 3 ETD01960 200 0.69 10 3 ETD01961 200 0.33 11 3 ETD01962 200 0.79

Minigene expression constructs encoding for wild type and rs117058816 (c.3+1G>A) MTRES1 proteins were generated. Minigene constructs (<10 kb) are easier to synthesize and have greater transfection efficiency in downstream experiments than constructs that exceed 10 kb in length. The minigene constructs have a portion of internal, intronic sequence removed, but retain all exons and UTRs. Therefore, the pre-mRNA of the exons, reduced introns, and 5′ and 3′ UTRs of the protein coding transcript (ENST00000625458) of MTRES1 was cloned into a pcDNA3.1 (+) vector driven by a CMV promoter. Empty vector was used as control. For rs117058816 expression constructs, the A allele replaced the G allele at DNA sequence position chr6: 107030108 (human genome build 38). This leads to the loss of a splice donor site (c.3+1G>A).

Transfections of HEK-293 cells were optimized. HEK-293 cells were plated in a 6-well plate in complete growth media and grown for 48 hours followed by a media change. Cells were then transfected with 2 μg of plasmid DNA and 7 μl of TransIT-2020. Cells were incubated for 48 hours, and then harvested.

1 FIG.A 1 FIG.B Cell lysates from transfected cells were assayed to evaluate intracellular MTRES1 protein by western blot (). In empty vector transfected HEK-293 cells, a faint band representing endogenous MTRES1 expression was detected by western blot as a band at 24 kDa. In cells transfected with the wild type construct, significant expression of MTRES1 was detected by western blot as a band 24 kDa. In cells transfected with the rs117058816 construct, reduced MTRES1 protein compared with wild type was detected by western blot as a band between 24 kDa. When normalizing to total protein, cells transfected with the rs117058816 construct express approximately 75% less MTRES1 protein compared with cells transfected with the wild type construct ().

2 FIG. Cell lysates from transfected cells were also assayed to evaluate MTRES1 mRNA by qPCR. Cells transfected with the rs117058816 construct express approximately 70% less MTRES1 mRNA compared with cells transfected with the wild type construct ().

These data provide experimental verification that MTRES1 gene variants associated with protection from dementia and Alzheimer's disease result in a change or loss of MTRES1 protein and MTRES1 mRNA abundance or function. Accordingly, in some cases therapeutic inhibition or modulation of MTRES1 may be an effective genetically-informed method of treatment for these diseases.

Sanger-verified CRISPR cell lines on a HEK-293 clonal background were generated including (i) a rs117058816-A (c.3+1A) homozygous knock-in (KI), a homozygous knock-out (KO) and a mock-transfected wild type (WT) cell line.

Cells were grown, fractionated and whole cell lysates and mitochondrial fractions harvested

3 FIG. Whole cell and mitochondrial fraction lysates from CRISPR cell lines were assayed to evaluate intracellular MTRES1 protein by western blot (). In WT cells, significant MTRES1 expression was detected by western blot as a band at 24 kDa in both whole cell lysates and mitochondrial fractions. In CRISPR KI cells, reduced MTRES1 protein compared with WT was detected by western blot in both whole cell lysates and mitochondrial fractions. In CRISPR KO cells, no MTRES1 protein was detected by western blot in either whole cell lysates or mitochondrial fractions.

4 FIG. Whole cell lysates from CRISPR cell lines were also assayed to evaluate MTRES1 mRNA by qPCR (). In CRISPR KI cells, approximately 70% less MTRES1 mRNA expression is observed compared with cells transfected with the wild type construct. In CRISPR KO cells, no MTRES1 mRNA expression was detected by qPCR.

These data provide further experimental verification that MTRES1 gene variants associated with protection from dementia and Alzheimer's disease result in loss of MTRES1 protein and MTRES1 mRNA abundance or function. Accordingly, in some cases therapeutic inhibition or modulation of MTRES1 may be an effective genetically-informed method of treatment for these diseases.

Oligonucleotides such as siRNAs may be synthesized according to phosphoramidite technology on a solid phase. For example, a K&A oligonucleotide synthesizer may be used. Syntheses may be performed on a solid support made of controlled pore glass (CPG, 500 Å or 600 Å, obtained from AM Chemicals, Oceanside, CA, USA). All 2′-OMe and 2′-F phosphoramidites may be purchased from Hongene Biotech (Union City, CA, USA). All phosphoramidites may be dissolved in anhydrous acetonitrile (100 mM) and molecular sieves (3 Å) may be added. 5-Benzylthio-1H-tetrazole (BTT, 250 mM in acetonitrile) or 5-Ethylthio-1H-tetrazole (ETT, 250 mM in acetonitrile) may be used as activator solution. Coupling times may be 9-18 min (e.g. with a GalNAc such as ETL17), 6 min (e.g. with 2′OMe and 2′F). In order to introduce phosphorothioate linkages, a 100 mM solution of 3-phenyl 1,2,4-dithiazoline-5-one (POS, obtained from PolyOrg, Inc., Leominster, Mass., USA) in anhydrous acetonitrile may be employed.

After solid phase synthesis, the dried solid support may be treated with a 1:1 volume solution of 40 wt. % methylamine in water and 28% ammonium hydroxide solution (Aldrich) for two hours at 30° C. The solution may be evaporated, and the solid residue may be reconstituted in water and purified by anionic exchange HPLC using a TKSgel SuperQ-5 PW 13u column. Buffer A may be 20 mM Tris, 5 mM EDTA, pH 9.0 and contained 20% Acetonitrile and buffer B may be the same as buffer A with the addition of 1 M sodium chloride. UV traces at 260 nm may be recorded. Appropriate fractions may be pooled then desalted using Sephadex G-25 medium.

Equimolar amounts of sense and antisense strand may be combined to prepare a duplex. The duplex solution may be prepared in 0.1×PBS (Phosphate-Buffered Saline, 1×, Gibco). The duplex solution may be annealed at 95° C. for 5 min, and cooled to room temperature slowly. Duplex concentration may be determined by measuring the solution absorbance on a UV-Vis spectrometer at 260 nm in 0.1×PBS. For some experiments, a conversion factor may be calculated from an experimentally determined extinction coefficient.

Without limiting the disclosure to these individual methods, there are at least two general methods for attachment of multivalent N-acetylgalactosamine (GalNAc) ligands to oligonucleotides: solid or solution-phase conjugations. GalNAc ligands may be attached to solid phase resin for 3′ conjugation or at the 5′ terminus using GalNAc phosphoramidite reagents. GalNAc phosphoramidites may be coupled on solid phase as for other nucleosides in the oligonucleotide sequence at any position in the sequence. Reagents for GalNAc conjugation to oligonucleotides are shown in Table 18.

TABLE 18 GalNAc Conjugation Reagents Type of conjugation Structure Solid phase 3′ attachment where squiggly line is the rest of oligonucleotide chain and right-most OH is where attachment to solid phase is. This GalNAc ligand may be referred to as “GalNAc23” or “GalNAc#23.” Solid phase 5′ attachment phosphoramidite Solid phase 5′ attachment Phosphoramidite Solution phase Carboxylic acid for amide coupling anywhere on oligonucleotide Where Ac is an acetyl group or other hydroxyl protecting group that can be removed under basic, acid or reducing conditions.

In solution phase conjugation, the oligonucleotide sequence-including a reactive conjugation site—is formed on the resin. The oligonucleotide is then removed from the resin and GalNAc is conjugated to the reactive site.

The carboxy GalNAc derivatives may be coupled to amino-modified oligonucleotides. The peptide coupling conditions are known to the skilled in the art using a carbodiimide coupling agent like DCC (N,N′-Dicyclohexylcarbodiimide), EDC (N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide) or EDC.HCl (N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and an additive like HOBt (1-hydroxybenztriazole), HOSu (N-hydroxysuccinimide), TBTU (N,N,N′,N′-Tetramethyl-O-(benzotriazol-1-yl) uronium tetrafluoroborate, HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) or HOAt (1-Hydroxy-7-azabenzotriazole and common combinations thereof such as TBTU/HOBt or HBTU/HOAt to form activated amine-reactive esters.

Amine groups may be incorporated into oligonucleotides using a number of known, commercially available reagents at the 5′ terminus, 3′ terminus or anywhere in between.

5′ attachment: 6-(4-Monomethoxytritylamino) hexyl-(2-cyanoethyl)-(N,N-diisopropyl)-phosphoramidite CAS Number: 114616-27-2 5′-Amino-Modifier TEG CE-Phosphoramidite 10-(O-trifluoroacetamido-N-ethyl)-triethyleneglycol-1-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite 3′ attachment: 3′-Amino-Modifier Serinol CPG 3-Dimethoxytrityloxy-2-(3-(fluorenylmethoxycarbonylamino) propanamido) propyl-1-O-succinyl-long chain alkylamino-CPG (where CPG stands for controlled-pore glass and is the solid support)· Amino-Modifier Serinol Phosphoramidite 3-Dimethoxytrityloxy-2-(3-(fluorenylmethoxycarbonylamino) propanamido) propyl-1-O-(2-cyanoethyl)-(N,N-diisopropyl)-phosphoramidite Non-limiting examples of reagents for oligonucleotide synthesis to incorporate an amino group include:

Amino-Modifier C6 dT 5′-Dimethoxytrityl-5-[N-(trifluoroacetylaminohexyl)-3-acrylimido]-2′-deoxyUridine,3′-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite. CAS Number: 178925-21-8

Solution phase conjugations may occur after oligonucleotide synthesis via reactions between non-nucleosidic nucleophilic functional groups that are attached to the oligonucleotide and electrophilic GalNAc reagents. Examples of nucleophilic groups include amines and thiols, and examples of electrophilic reagents include activated esters (e.g. N-hydroxysuccinimide, pentafluorophenyl) and maleimides.

Without limiting the disclosure to these individual methods, there are at least two general methods for attachment of multivalent N-acetylgalactosamine (GalNAc) ligands to oligonucleotides: solid or solution-phase conjugations. GalNAc ligands may be attached to solid phase resin for 3′ conjugation or at the 5′ terminus using GalNAc phosphoramidite reagents. GalNAc phosphoramidites may be coupled on solid phase as for other nucleosides in the oligonucleotide sequence at any position in the sequence. A non-limiting example of a phosphoramidite reagent for GalNAc conjugation to a 5′ end oligonucleotide is shown in Table 19.

TABLE 19 GalNAc Conjugation Reagent Type of conjugation Structure Solid phase 5′ attachment phos- phoramidite

The following includes examples of synthesis reactions used to create a GalNAc moiety:

2 f 1 To a solution of Compound 1A (500 g, 4.76 mol, 476 mL) in 2-Methly-THF (2.00 L) is added CbzCl (406 g, 2.38 mol, 338 mL) in 2-Methyl-THF (750 mL) dropwise at 0° C. The mixture is stirred at 25° C. for 2 hours under Natmosphere. TLC (DCM:MeOH=20:1, PMA) may indicate CbzCl is consumed completely and one new spot (R=0.43) formed. The reaction mixture is added HCl/EtOAc (1 N, 180 mL) and stirred for 30 mins, white solid is removed by filtration through celite, the filtrate is concentrated under vacuum to give Compound 2A (540 g, 2.26 mol, 47.5% yield) as a pale-yellow oil and used into the next step without further purification.H NMR: δ 7.28-7.41 (m, 5H), 5.55 (br s, 1H), 5.01-5.22 (m, 2H), 3.63-3.80 (m, 2H), 3.46-3.59 (m, 4H), 3.29-3.44 (m, 2H), 2.83-3.02 (m, 1H).

2 2 f To a solution of Compound 3A (1.00 kg, 4.64 mol, HCl) in pyridine (5.00 L) is added acetyl acetate (4.73 kg, 46.4 mol, 4.34 L) dropwise at 0° C. under Natmosphere. The mixture is stirred at 25° C. for 16 hrs under Natmosphere. TLC (DCM:MeOH=20:1, PMA) indicated Compound 3A is consumed completely and two new spots (R=0.35) formed. The reaction mixture is added to cold water (30.0 L) and stirred at 0° C. for 0.5-hour, white solid formed, filtered and dried to give Compound 4A (1.55 kg, 3.98 mol, 85.8% yield) as a white solid and used in the next step without further purification. 1H NMR: δ 7.90 (d, J=9.29 Hz, 1H), 5.64 (d, J=8.78 Hz, 1H), 5.26 (d, J=3.01 Hz, 1H), 5.06 (dd, J=11.29, 3.26 Hz, 1H), 4.22 (t, J=6.15 Hz, 1H), 3.95-4.16 (m, 3H), 2.12 (s, 3H), 2.03 (s, 3H), 1.99 (s, 3H), 1.90 (s, 3H), 1.78 (s, 3H).

2 2 f 3 2 4 1 To a solution of Compound 4A (300 g, 771 mmol) in DCE (1.50 L) is added TMSOTf (257 g, 1.16 mol, 209 mL) and stirred for 2 hrs at 60° C., and then stirred for 1 hour at 25° C. Compound 2A (203 g, 848 mmol) is dissolved in DCE (1.50 L) and added 4 Å powder molecular sieves (150 g) stirring for 30 mins under Natmosphere. Then the solution of Compound 4A in DCE is added dropwise to the mixture at 0° C. The mixture is stirred at 25° C. for 16 hrs under Natmosphere. TLC (DCM:MeOH=25:1, PMA) indicated Compound 4A is consumed completely and new spot (R=0.24) formed. The reaction mixture is filtered and washed with sat. NaHCO(2.00 L), water (2.00 L) and sat. brine (2.00 L). The organic layer is dried over anhydrous NaSO, filtered and concentrated under reduced pressure to give a residue. The residue is triturated with 2-Me-THE/heptane (5/3, v/v, 1.80 L) for 2 hrs, filtered and dried to give Compound 5A (225 g, 389 mmol, 50.3% yield, 98.4% purity) as a white solid.H NMR: δ 7.81 (d, J=9.29 Hz, 1H), 7.20-7.42 (m, 6H), 5.21 (d, J=3.26 Hz, 1H), 4.92-5.05 (m, 3H), 4.55 (d, J=8.28 Hz, 1H), 3.98-4.07 (m, 3H), 3.82-3.93 (m, 1H), 3.71-3.81 (m, 1H), 3.55-3.62 (m, 1H), 3.43-3.53 (m, 2H), 3.37-3.43 (m, 2H), 3.14 (q, J=5.77 Hz, 2H), 2.10 (s, 3H), 1.99 (s, 3H), 1.89 (s, 3H), 1.77 (s, 3H).

2 2 2 f 1 To a solution of Compound 5A (200 g, 352 mmol) in THF (1.0 L) is added dry Pd/C (15.0 g, 10% purity) and TsOH (60.6 g, 352 mmol) under Natmosphere. The suspension is degassed under vacuum and purged with Hseveral times. The mixture is stirred at 25° C. for 3 hrs under H(45 psi) atmosphere. TLC (DCM:MeOH=10:1, PMA) indicated Compound 5A is consumed completely and one new spot (R=0.04) is formed. The reaction mixture is filtered and concentrated (≤40° C.) under reduced pressure to give a residue. Diluted with anhydrous DCM (500 mL, dried overnight with 4 Å molecular sieves (dried at 300° C. for 12 hrs)) and concentrate to give a residue and run Karl Fisher (KF) to check for water content. This is repeated 3 times with anhydrous DCM (500 mL) dilutions and concentration to give NAcegal-Linker-TMSOTf (205 g, 95.8% yield, TsOH salt) as a foamy white solid.H NMR: δ 7.91 (d, J=9.03 Hz, 1H), 7.53-7.86 (m, 2H), 7.49 (d, J=8.03 Hz, 2H), 7.13 (d, J=8.03 Hz, 2H), 5.22 (d, J=3.26 Hz, 1H), 4.98 (dd, J=11.29, 3.26 Hz, 1H), 4.57 (d, J=8.53 Hz, 1H), 3.99-4.05 (m, 3H), 3.87-3.94 (m, 1H), 3.79-3.85 (m, 1H), 3.51-3.62 (m, 5H), 2.96 (br t, J=5.14 Hz, 2H), 2.29 (s, 3H), 2.10 (s, 3H), 2.00 (s, 3H), 1.89 (s, 3H), 1.78 (s, 3H).

2 4 2 To a solution of Compound 4B (400 g, 1.67 mol, 1.00 eq) and NaOH (10 M, 16.7 mL, 0.10 eq) in THF (2.00 L) is added Compound 4B_2 (1.07 kg, 8.36 mol, 1.20 L, 5.00 eq), the mixture is stirred at 30° C. for 2 hrs. LCMS showed the desired MS is given. Five batches of solution are combined to one batch, then the mixture is diluted with water (6.00 L), extracted with ethyl acetate (3.00 L*3), the combined organic layer is washed with brine (3.00 L), dried over NaSO, filtered and concentrated under vacuum. The crude is purified by column chromatography (SiO, petroleum ether:ethyl acetate=100:1-10:1, R (=0.5) to give Compound 5B (2.36 kg, 6.43 mol, 76.9% yield) as light-yellow oil. HNMR: δ 7.31-7.36 (m, 5H), 5.38 (s, 1H), 5.11-5.16 (m, 2H), 3.75 (t, J=6.4 Hz), 3.54-3.62 (m, 6H), 3.39 (d, J=5.2 Hz), 2.61 (t, J=6.0 Hz).

2 4 1 To a solution of Compound 5B (741 g, 2.02 mol, 1.00 eq) in DCM (2.80 L) is added TFA (1.43 kg, 12.5 mol, 928 mL, 6.22 eq), the mixture is stirred at 25° C. for 3 hrs. LCMS showed the desired MS is given. The mixture is diluted with DCM (5.00 L), washed with water (3.00 L*3), brine (2.00 L), the combined organic layer is dried over NaSO, filtered and concentrated under vacuum to give Compound 2B (1800 g, crude) as light-yellow oil.H NMR: δ 9.46 (s, 5H), 7.27-7.34 (m, 5H), 6.50-6.65 (m, 1H), 5.71 (s, 1H), 5.10-5.15 (m, 2H), 3.68-3.70 (m, 14H), 3.58-3.61 (m, 6H), 3.39 (s, 2H), 2.55 (s, 6H), 2.44 (s, 2H).

2 3 2 4 To a solution of Compound 2B (375 g, 999 mmol, 83.0% purity, 1.00 eq) in DCM (1.80 L) is added HATU (570 g, 1.50 mol, 1.50 eq) and DIEA (258 g, 2.00 mol, 348 mL, 2.00 eq) at 0° C., the mixture is stirred at 0° C. for 30 min, then Compound 1B (606 g, 1.20 mol, 1.20 eq) is added, the mixture is stirred at 25° C. for 1 hr. LCMS showed desired MS is given. The mixture is combined to one batch, then the mixture is diluted with DCM (5.00 L), washed with 1 N HCl aqueous solution (2.00 L*2), then the organic layer is washed with saturated NaCOaqueous solution (2.00 L*2) and brine (2.00 L), the organic layer is dried over NaSO, filtered and concentrated under vacuum to give Compound 3B (3.88 kg, crude) as yellow oil.

2 4 2 f 2 4 A solution of Compound 3B (775 g, 487 mmol, 50.3% purity, 1.00 eq) in HCl/dioxane (4 M, 2.91 L, 23.8 eq) is stirred at 25° C. for 2 hrs. LCMS showed the desired MS is given. The mixture is concentrated under vacuum to give a residue. Then the combined residue is diluted with DCM (5.00 L), adjusted to pH=8 with 2.5 M NaOH aqueous solution, and separated. The aqueous phase is extracted with DCM (3.00 L) again, then the aqueous solution is adjusted to pH=3 with 1 N HCl aqueous solution, then extracted with DCM (5.00 L*2), the combined organic layer is washed with brine (3.00 L), dried over NaSO, filtered and concentrated under vacuum. The crude is purified by column chromatography (SiO, DCM:MeOH=0:1-12:1, 0.1% HOAc, R=0.4). The residue is diluted with DCM (5.00 L), adjusted to pH=8 with 2.5 M NaOH aqueous solution, separated, the aqueous solution is extracted with DCM (3.00 L) again, then the aqueous solution is adjusted to pH=3 with 6 N HCl aqueous solution, extracted with DCM:MeOH=10:1 (5.00 L*2), the combined organic layer is washed with brine (2.00 L), dried over NaSO, filtered and concentrated under vacuum to give a residue. Then the residue is diluted with MeCN (5.00 L), concentrated under vacuum, repeat this procedure twice to remove water to give TRIS-PEG2-CBZ (1.25 kg, 1.91 mol, 78.1% yield, 95.8% purity) as light-yellow oil. 1HNMR: 400 MHZ, MeOD, δ 7.30-7.35 (5H), 5.07 (s, 2H), 3.65-3.70 (m, 16H), 3.59 (s, 4H), 3.45 (t, J=5.6 Hz), 2.51 (t, J=6.0 Hz), 2.43 (t, 6.4 Hz).

Scheme for the preparation of TriNGal-TRIS-Peg2-Phosph 8c

3 To a solution of Compound 1C (155 g, 245 mmol, 1.00 eq) in ACN (1500 mL) is added TBTU (260 g, 811 mmol, 3.30 eq), DIEA (209 g, 1.62 mol, 282 mL, 6.60 eq) and Compound 2C (492 g, 811 mmol, 3.30 eq, TsOH) at 0° C., the mixture is stirred at 15° C. for 16 hrs. LCMS showed the desired MS is given. The mixture is concentrated under vacuum to give a residue, then the mixture is diluted with DCM (2000 mL), washed with 1 N HCl aqueous solution (700 mL*2), then saturated NaHCOaqueous solution (700 mL*2) and concentrated under vacuum. The crude is purified by column chromatography to give Compound 3C (304 g, 155 mmol, 63.1% yield, 96.0% purity) as a yellow solid.

2 2 Two batches solution of Compound 3C (55.0 g, 29.2 mmol, 1.00 eq) in MeOH (1600 mL) is added Pd/C (6.60 g, 19.1 mmol, 10.0% purity) and TFA (3.34 g, 29.2 mmol, 2.17 mL, 1.00 eq), the mixture is degassed under vacuum and purged with H. The mixture is stirred under H(15 psi) at 15° C. for 2 hours. LCMS showed the desired MS is given. The mixture is filtered and the filtrate is concentrated under vacuum to give Compound 4C (106 g, 54.8 mmol, 93.7% yield, 96.2% purity, TFA) as a white solid.

f 3 2 4 2 2 f Two batches in parallel. To a solution of EDCI (28.8 g, 150 mmol, 1.00 eq) in DCM (125 mL) is added compound 4a (25.0 g, 150 mmol, 1.00 eq) dropwise at 0° C., then the mixture is added to compound 4 (25.0 g, 150 mmol, 1.00 eq) in DCM (125 mL) at 0° C., then the mixture is stirred at 25° C. for 1 hr. TLC (Petroleum ether:Ethyl acetate=3:1, R=0.45) showed the reactant is consumed and one new spot is formed. The reaction mixture is diluted with DCM (100 mL) then washed with aq. NaHCO(250 mL*1) and brine (250 mL), dried over NaSO, filtered and concentrated under reduced pressure to give a residue. The residue is purified by column chromatography (SiO, Petroleum ether:Ethyl acetate=100:1 to 3:1), TLC (SiO, Petroleum ether:Ethyl acetate=3:1), R=0.45, then concentrated under reduced pressure to give a residue. Compound 5C (57.0 g, 176 mmol, 58.4% yield, 96.9% purity) is obtained as colorless oil and confirmed 1HNMR: EW33072-2-PIA, 400 MHZ, DMSO & 9.21 (s, 1H), 7.07-7.09 (m, 2H), 6.67-6.70 (m, 2H), 3.02-3.04 (m, 2H), 2.86-2.90 (m, 2H).

3 2 3 2 4 To a mixture of compound 3 (79.0 g, 41.0 mmol, 96.4% purity, 1.00 eq, TFA) and compound 6C (14.2 g, 43.8 mmol, 96.9% purity, 1.07 eq) in DCM (800 mL) is added TEA (16.6 g, 164 mmol, 22.8 mL, 4.00 eq) dropwise at 0° C., and the mixture is stirred at 15° C. for 16 hrs. LCMS (EW33072-12-P1B, Rt=0.844 min) showed the desired mass is detected. The reaction mixture is diluted with DCM (400 mL) and washed with aq. NaHCO(400 mL*1) and brine (400 mL*1), then the mixture is diluted with DCM (2.00 L) and washed with 0.7 M NaCO(1000 mL*3) and brine (800 mL*3), dried over NaSO, filtered and concentrated under reduced pressure to give a residue. The residue is used to next step directly without purification. Compound 6 (80.0 g, crude) is obtained as white solid and confirmed via 1HNMR: EW33072-12-PIA, 400 MHz, MeOD δ 7.02-7.04 (m, 2H), 6.68-6.70 (m, 2H), 5.34-5.35 (s, 3H), 5.07-5.08 (d, J=4.00 Hz, 3H), 4.62-4.64 (d, J=8.00 Hz, 3H), 3.71-4.16 (m, 16H), 3.31-3.70 (m, 44H), 2.80-2.83 (m, 2H), 2.68 (m, 2H), 2.46-2.47 (m, 10H), 2.14 (s, 9H), 2.03 (s, 9H), 1.94-1.95 (d, J=4.00 Hz, 18H).

3 2 2 2 4 2 2 f Two batches are synthesized in parallel. To a solution of compound 6C (40.0 g, 21.1 mmol, 1.00 eq in DCM (600 mL) is added diisopropylammonium tetrazolide (3.62 g, 21.1 mmol, 1.00 eq) and compound 7c (6.37 g, 21.1 mmol, 6.71 mL, 1.00 eq) in DCM (8.00 mL) drop-wise, the mixture is stirred at 30° C. for 1 hour, then added compound 7c (3.18 g, 10.6 mmol, 3.35 mL, 0.50 eq) in DCM (8.00 mL) drop-wise, the mixture is stirred at 30° C. for 30 mins, then added compound 7c (3.18 g, 10.6 mmol, 3.35 mL, 0.50 eq) in DCM (8.00 mL) drop-wise, the mixture is stirred at 30° C. for 1.5 hrs. LCMS (EW33072-17-P1C1, Rt=0.921 min) showed the desired MS+1 is detected. LCMS (EW33072-17-P1C2, Rt=0.919 min) showed the desired MS+1 is detected. Two batches are combined for work-up. The mixture is diluted with DCM (1.20 L), washed with saturated NaHCOaqueous solution (1.60 L*2), 3% DMF in HO (1.60 L*2), HO (1.60 L*3), brine (1.60 L), dried over NaSO, filtered and concentrated under reduced pressure to give a residue. The residue is purified by column chromatography (SiO, DCM:MeOH:TEA=100:3:2) TLC (SiO, DCM:MeOH=10:1, R=0.45), then concentrated under reduced pressure to give a residue. Compound 8C (76.0 g, 34.8 mmol, 82.5% yield, 96.0% purity) is obtained as white solid and confirmed via 1HNMR: EW33072-19-PIC, 400 MHZ, MeOD δ 7.13-7.15 (d, J=8.50 Hz, 2H), 6.95-6.97 (dd, J=8.38, 1.13 Hz, 2H), 5.34 (d, J=2.88 Hz, 3H), 0.09 (dd, J=11.26, 3.38 Hz, 3H), 4.64 (d, J=8.50 Hz, 3H), 3.99-4.20 (m, 12H), 3.88-3.98 (m, 5H), 3.66-3.83 (m, 20H), 3.51-3.65 (m, 17H), 3.33-3.50 (m, 9H), 2.87 (t, J=7.63 Hz, 2H), 2.76 (t, J=5.94 Hz, 2H), 2.42-2.50 (m, 10H), 2.14 (s, 9H), 2.03 (s, 9H), 1.94-1.95 (d, J=6.13 Hz, 18H), 1.24-1.26 (d, J=6.75 Hz, 6H), 1.18-1.20 (d, J=6.75 Hz, 6H)

Position 9 (from 5′ to 3′) of the sense strand is 2′-F. If position 9 is a pyrimidine, then all purines in the Sense Strand are 2′OMe, and 1-5 pyrimidines between positions 5 and 11 are 2′-F provided that there are never three 2′F modifications in a row. If position 9 is a purine, then all pyrimidines in the Sense Strand are 2′OMe, and 1-5 purines between positions 5 and 11 are 2′-F provided that there are never three 2′F modifications in a row. Antisense strand odd-numbered positions are 2′OMe and even-numbered positions are a mixture of 2′-F, 2′-OMe and 2′-deoxy. An example MTRES1 siRNA includes a combination of the following modifications:

Position 9 (from 5′ to 3′) of the sense strand is 2′-deoxy. Sense strand positions 5, 7 and 8 are 2′-F. All pyrimidines in positions 10-21 are 2′-OMe, and purines are a mixture of 2′-OMe and 2′-F. Alternatively, all purines in positions 10-21 are 2′-OMe and all pyrimidines in positions 10-21 are a mixture of 2′-OMe and 2′-F. Antisense strand odd-numbered positions are 2′OMe and even-numbered positions are a mixture of 2′-F, 2′OMe and 2′-deoxy. An example MTRES1 siRNA includes a combination of the following modifications:

The major common genetic risk factor for Alzheimer's disease is the APOE haplotype, with permutations of 2 genetic variants, rs429358 (p.Cys112Arg) and rs7412 (p.Arg158Cys) defining 3 major APOE haplotypes-E2, E3 and E4 (Table 20). The APOE2 haplotype is considered protective, APOE3 haplotype is considered ‘neutral’ and APOE4 haplotype is considered risk for Alzheimer's disease and dementia.

TABLE 20 APOE alleles and haplotypes APOE Allele ε2 ε3 ε4 Haplotype rs429358-T rs429358-T rs429358-C (p.112Cys) (p.112Cys) (p.112Arg) rs7412-T rs7412-C rs7412-C (p.158Cys) (p.158Arg) (p.158Arg)

Stratified genetic analyses were performed to evaluate the effect of the MTRES1 rs117058816 splice donor variant (c.3+1G>A) on an APOE4 risk background in 452,401 individuals with genotype data from the UK Biobank cohort. All stratified analyses were performed under the assumption that the APOE3 haplotype and the MTRES1 rs117058816 (c.3+1G>A) reference (G) alleles are ‘neutral’, therefore the reference group in these analyses consists of individuals who are MTRES1 rs117058816 (c.3+1G>A) G/G and APOE E3/E3.

In addition to replicating the well-known association between APOE4 and significantly increased risk of dementia, the analyses indicate that APOE4 homozygous individuals that carry a single copy of MTRES1 rs117058816-A (c.3+1A) alternative (A) allele have approximately half the relative risk of dementia compared with APOE4 homozygous individuals that are homozygous for the MTRES1 rs117058816-G (c.3+1G) reference (G) allele (Table 21).

TABLE 21 APOE4 and MTRES1 rs117058816 (c.3 + 1G > A) stratified analyses Dementia (n = 4,009) Variant Gene EAF P value OR APOE4/E4 Relative Risk E4/E4 vs. E3/E3 APOE 0.02 <5E−324 ↑10.688 1 G/G E4/E4 vs. G/G E3/E3 MTRES1/APOE 0.02 <5E−324 ↑10.652 0.997 G/A E4/E4 vs. G/G E3/E3 MTRES1/APOE 0.003 0.003 ↑5.412 ↓0.506

These results indicate that loss-of-function of MTRES1 results in protection from dementia even in the context of the exceptionally high genetic risk conferred by APOE4 homozygosity. These results further indicate that therapeutic inhibition of MTRES1 may result in similar disease-protective effects in APOE4 heterozygous and homozygous carriers at increased genetic risk of Alzheimer's disease and dementia.

Polygenic risk scores (PRS) are increasingly being utilized in the screening, diagnosis and treatment of disease. PRS aggregate the effects (or weights) of a large number of genetic variants on a given disease to estimate an individual's risk for that disease. Those individuals within the highest percentiles of the score tend to have a higher incidence of the disease as compared to individuals in the percentiles below, and this information can be utilized in both clinical and research settings to select individuals most likely to benefit from a diagnostic test or therapeutic intervention.

A PRS score was generated using publicly available weights from 37 independent genetic variants, with a p value less than 1e-5 within a meta-analysis of Alzheimer's disease (PGS catalogue-PGS000898). Notably, this set of variants did not include the APOE locus, allowing examination of APOE-independent polygenic risk for Alzheimer's. The PRS score was calculated for 452,401 individuals with genotype data from the UK Biobank cohort, multiplying weights by the number of alternative alleles, and summing across all variants per individual. Examining model performance, individuals in the upper 20th percentile of PRS scores were 1.68 times more likely to have all cause dementia as compared to those in the remaining 80% of samples.

Genetic analyses were performed to evaluate the effect of the MTRES1 rs117058816 splice donor variant (c.3+1G>A) on the risk of dementia in the full sample of 452,401 UK Biobank participants and in subsetted strata comprising the upper 20th and 40th percentiles of the Alzheimer's disease PRS (90,492 participants and 158,331 participants respectively).

The analyses indicate that the MTRES1 rs117058816 splice donor variant (c.3+1G>A) is associated with protection from dementia in all individuals and in individuals at high polygenic risk of Alzheimer's disease, with a notable increase in the already large protective effect size as the polygenic risk increases (allelic odds ratios of 0.489, 0.337, and 0.291 among all individuals and individuals in the top 40th and 20th percentiles for PRS risk respectively) (Table 22).

TABLE 22 MTRES1 rs117058816 (c.3 + 1G > A) associations within Alzheimer's Disease PRS strata Dementia (n = 4,009) Variant Gene PRS Strata N in Strata P value OR rs117058816 (c.3 + 1G > A) MTRES1 None (all individuals) 452,401 7.92E−07 ↓0.489 rs117058816 (c.3 + 1G > A) MTRES1 th Upper 40Percentile 158,331 7.07E−07 ↓0.337 rs117058816 (c.3 + 1G > A) MTRES1 th Upper 20Percentile 90,492 3.14E−05 ↓0.291

These results indicate that in the context of APOE-independent, high polygenic risk for Alzheimer's disease, MTRES1 loss-of-function confers protection from dementia. These results further indicate that therapeutic inhibition of MTRES1 may result in similar disease-protective effects in individuals with high polygenic risk for Alzheimer's disease and dementia.

Several GalNAc-conjugated siRNAs designed to be cross-reactive with at least human and mouse MTRES1 mRNA were tested for activity in mice. The siRNAs contained either GalNAc ligand ETL1 or ETL17. The siRNA sequences are shown in Table 23, where Nf is a 2′-fluoro-modified nucleoside, n is a 2′-O-methyl modified nucleoside, “d” is a deoxynucleoside, and “s” is a phosphorothioate linkage. Base sequences are shown in Tables 24-25.

Six- to eight-week-old female mice (strain ICR, n=3) were given a subcutaneous injection on Day 0 of a single 100 μg dose of a GalNAc-conjugated siRNA or PBS as vehicle control. ETD01944 targeting mouse MTRES1 mRNA was included as a positive control.

Mice were euthanized on Day 10 after injection and a liver sample from each was collected and placed in RNAlater (ThermoFisher Catalog #AM7020) until processing. Total liver RNA was prepared by homogenizing the liver tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer's recommendations. Preparation of cDNA was performed using Quanta qScript cDNA SuperMix (VWR, Catalog #95048-500) according to the manufacturer's instructions. The relative levels of liver MTRES1 mRNA were assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for mouse MTRES1 (ThermoFisher, assay #Mm01229834_m1) and the mouse housekeeping gene PPIA (ThermoFisher, assay #Mm02342430_g1) and PerfeCTaR qPCR FastMix®, Low ROX™ (VWR, Catalog #101419-222). Data were normalized to the mean MTRES1 mRNA level in animals receiving PBS. Results are shown in Table 26. Mice receiving ETD01597, ETD02075 and ETD02077 had the highest level of mean MTRES1 mRNA knockdown in the liver.

TABLE 23 Example siRNA Sequences Anti- Sense sense Strand Strand siRNA SEQ ID Sense Strand Sequence  SEQ ID Antisense Strand Sequence Name NO: (5′-3′) with GalNAc moiety NO: (5′-3′) ETD01507 3038 [ETL1]csus AfcAfaAfgGfuGfa 3125 usCfsugaGfuUfcaccuUfuGfua AfcucAfgAfsusu gsusu ETD01944 3039 [ETL17]sagcaAfuAfuAfAfacuc 3126 usUfsuUfgGfaGfuUfuAfuAfu caaaasusu UfgCfususu ETD01955 3040 [ETL17]scuuccuGfGfAfAfucga 3127 usAfsgUfaUfcGfaUfuCfcAfg uacuasusu GfaAfgsusu ETD02071 3041 [ETL17]suuccuGfGfAfAfucga 3128 usAfsaGfuAfuCfgAfuUfcCfa uacuuasusu GfgAfasusu ETD02072 3042 [ETL17]succuGfgAfAfdUCfga 3129 usCfsaAfgUfaUfcGfaUfuCfc uacuugasusu AfgGfasusu ETD02073 3043 [ETL17]sccugGfaAfUfdCgaua 3130 usAfscAfaGfuAfuCfgAfuUfc cuuguasusu CfaGfgsusu ETD02074 3044 [ETL17]suuguaUfUfUfUfUfcu 3131 usGfsgUfaCfuAfgAfaAfaAfu aguaccasusu AfcAfasusu ETD02075 3045 [ETL17]sucuacAfAfAfGfGfug 3132 usUfsgAfgUfuCfaCfcUfuUfg aacucaasusu UfaGfasusu ETD02076 3046 [ETL17]scaaaGfGfuGfAfacuca 3133 usAfsgCfcUfgAfgUfuCfaCfc ggcuasusu UfuUfgsusu ETD02077 3047 [ETL17]sgaagAfAfAfAfGfcag 3134 usAfscCfgUfuCfuGfcUfuUfu aacgguasusu CfuUfcsusu ETD02078 3048 [ETL17]saagaAfaAfGfdCagaac 3135 usCfsaCfcGfuUfcUfgCfuUfu ggugasusu UfcUfususu ETD02079 3049 [ETL17]sgaaaAfGfcAfGfaAfcg 3136 usUfsuCfaCfcGfuUfcUfgCfu gugaaasusu UfuUfcsusu ETD02080 3050 [ETL17]scagaAfcGfGfdUgaaa 3137 usCfscCfaCfuUfuCfaCfcGfuU gugggasusu fcUfgsusu

TABLE 24 Example siRNA Base Sequences SEQ SEQ siRNA ID Sense Strand Base  ID Antisense Strand Base Name NO: Sequence (5′ to 3′) NO: Sequence (5′ to 3′) ETD01507 2674 CUACAAAGGUGAACUCAGAUU 2856 UCUGAGUUCACCUUUGUAGUU ETD01944 2675 AGCAAUAUAAACUCCAAAAUU 2857 UUUUGGAGUUUAUAUUGCUUU ETD01955 2676 CUUCCUGGAAUCGAUACUAUU 2858 UAGUAUCGAUUCCAGGAAGUU ETD02071 2677 UUCCUGGAAUCGAUACUUAUU 2859 UAAGUAUCGAUUCCAGGAAUU ETD02072 2678 UCCUGGAAUCGAUACUUGAUU 2860 UCAAGUAUCGAUUCCAGGAUU ETD02073 2679 CCUGGAAUCGAUACUUGUAUU 2861 UACAAGUAUCGAUUCCAGGUU ETD02074 2680 UUGUAUUUUUCUAGUACCAUU 2862 UGGUACUAGAAAAAUACAAUU ETD02075 2681 UCUACAAAGGUGAACUCAAUU 2863 UUGAGUUCACCUUUGUAGAUU ETD02076 2682 CAAAGGUGAACUCAGGCUAUU 2864 UAGCCUGAGUUCACCUUUGUU ETD02077 2683 GAAGAAAAGCAGAACGGUAUU 2865 UACCGUUCUGCUUUUCUUCUU ETD02078 2684 AAGAAAAGCAGAACGGUGAUU 2866 UCACCGUUCUGCUUUUCUUUU ETD02079 2685 GAAAAGCAGAACGGUGAAAUU 2867 UUUCACCGUUCUGCUUUUCUU ETD02080 2686 CAGAACGGUGAAAGUGGGAUU 2868 UCCCACUUUCACCGUUCUGUU

TABLE 25 Example siRNA Base Sequences without 3′ overhangs SEQ Sense Strand Base SEQ Antisense Strand Base siRNA ID Sequence (5′ to 3′), ID Sequence (5′ to 3′),  Name NO: without 3′ overhangs NO: without 3′ overhangs ETD01507 2688 CUACAAAGGUGAACUCAGG 2870 UCUGAGUUCACCUUUGUAG ETD01944 2689 AGCAAUAUAAACUCCAAAA 2871 UUUUGGAGUUUAUAUUGCU ETD01955 2690 CUUCCUGGAAUCGAUACUU 2872 UAGUAUCGAUUCCAGGAAG ETD02071 2691 UUCCUGGAAUCGAUACUUG 2873 UAAGUAUCGAUUCCAGGAA ETD02072 2692 UCCUGGAAUCGAUACUUGU 2874 UCAAGUAUCGAUUCCAGGA ETD02073 2693 CCUGGAAUCGAUACUUGUA 2875 UACAAGUAUCGAUUCCAGG ETD02074 2694 UUGUAUUUUUCUAGUACCA 2876 UGGUACUAGAAAAAUACAA ETD02075 2695 UCUACAAAGGUGAACUCAG 2877 UUGAGUUCACCUUUGUAGA ETD02076 2696 CAAAGGUGAACUCAGGCUG 2878 UAGCCUGAGUUCACCUUUG ETD02077 2697 GAAGAAAAGCAGAACGGUG 2879 UACCGUUCUGCUUUUCUUC ETD02078 2698 AAGAAAAGCAGAACGGUGA 2880 UCACCGUUCUGCUUUUCUU ETD02079 2699 GAAAAGCAGAACGGUGAAA 2881 UUUCACCGUUCUGCUUUUC ETD02080 2700 CAGAACGGUGAAAGUGGGA 2882 UCCCACUUUCACCGUUCUG

TABLE 26 Relative MTRES1 mRNA Levels in Livers of Mice Dose Mean MTRES1 mRNA (Normalized Group n Treatment (ug) to Group 1, Day 10) 1 3 PBS 1 2 3 ETD01507 100 0.03 3 3 ETD01944 100 0.27 4 3 ETD01955 100 0.27 5 3 ETD02071 100 0.92 6 3 ETD02072 100 0.77 7 3 ETD02073 100 0.76 8 3 ETD02074 100 0.73 9 3 ETD02075 100 0.18 10 3 ETD02076 100 0.6 11 3 ETD02077 100 0.18

The base sequences of ETD02075 and ETD2077 were synthesized with alternative modification patterns and then tested for activity in mice. The siRNA sequences are shown in Table 27, where Nf is a 2′-fluoro-modified nucleoside, n is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate linkage. All siRNAs were conjugated to the GalNAc ligand ETL17. Base sequences are shown in Table 28.

Six- to eight-week-old female mice (strain ICR, n=3) were given a subcutaneous injection on Day 0 of a single 100 μg dose of a GalNAc-conjugated siRNA or PBS as vehicle control.

Mice were euthanized on Day 14 after injection and a liver sample from each was collected and placed in RNAlater (ThermoFisher Catalog #AM7020) until processing. Total liver RNA was prepared by homogenizing the liver tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer's recommendations. Preparation of cDNA was performed using Quanta qScript cDNA SuperMix (VWR, Catalog #95048-500) according to the manufacturer's instructions. The relative levels of liver MTRES1 mRNA were assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for mouse MTRES1 (ThermoFisher, assay #Mm01229834_m1) and the mouse housekeeping gene PPIA (ThermoFisher, assay #Mm02342430_g1) and PerfeCTa® qPCR FastMix®, Low ROX™ (VWR, Catalog #101419-222). Data were normalized to the mean MTRES1 mRNA level in animals receiving PBS. Results are shown in Table 29. Of the alternatively modified versions of ETD02075, mice receiving ETD02182, ETD02183 and ETD02185 had the highest level of mean MTRES1 mRNA knockdown in the liver. Of the alternatively modified versions of ETD02077, mice receiving ETD02189 and ETD02192 had the highest level of mean MTRES1 mRNA knockdown in the liver.

TABLE 27 Example siRNA Sequences Sense Antisense Strand Sense Strand Strand SiRNA SEQ ID Sequence (5′-3′) SEQ ID Antisense Strand Sequence Name NO: with GalNAc moiety NO: (5′-3′) ETD02075 3051 [ETL17]sucuacAfAfAfGfGfug 3138 usUfsgAfgUfuCfaCfcUfuUfg aacucaasusu UfaGfasusu ETD02179 3052 [ETL17]sucuacaAfAfGfGfugaa 3139 usUfsgAfgUfuCfaCfcUfuUfg cucaasusu UfaGfasusu ETD02180 3053 [ETL17]sucuacaAfAfGfGfuGf 3140 usUfsgAfgUfuCfaCfcUfuUfg aacucaasusu UfaGfasusu ETD02181 3054 [ETL17]sucuacAfAfAfGfGfug 3141 usUfsgagUfuCfaCfcuuUfgUfa aacucaasusu Gfasusu ETD02182 3055 [ETL17]sucuacAfAfAfGfGfug 3142 usUfsgagUfuCfaCfcUfuUfgUf aacucaasusu aGfasusu ETD02183 3056 [ETL17]sucuacAfAfAfGfGfug 3143 usUfsgaGfuUfcaCfcUfuUfgUf aacucaasusu aGfasusu ETD02184 3057 [ETL17]sucuacAfAfAfGfGfug 3144 usUfsgaGfuUfcAfccuuUfgUfa aacucaasusu Gfasusu ETD02185 3058 [ETL17]sucuacAfAfAfGfGfug 3145 usUfsgAfguUfcAfccuuUfgUfa aacucaasusu Gfasusu ETD02186 3059 [ETL17]sucuacAfAfAfGfgugaa 3146 usUfsgAfgUfuCfaCfcuuUfgU cucaasusu faGfasusu ETD02077 3060 [ETL17]sgaagAfAfAfAfGfcag 3147 usAfscCfgUfuCfuGfcUfuUfu aacgguasusu CfuUfcsusu ETD02187 3061 [ETL17]sgaagaAfAfAfGfcagaa 3148 usAfscCfgUfuCfuGfcUfuUfu cgguasusu CfuUfcsusu ETD02188 3062 [ETL17]sgaagaAfAfAfGfcAfg 3149 usAfscCfgUfuCfuGfcUfuUfu aacgguasusu CfuUfcsusu ETD02189 3063 [ETL17]sgaagAfAfAfAfGfcag 3150 usAfsccgUfuCfuGfcUfuUfuCf aacgguasusu uUfcsusu ETD02190 3064 [ETL17]sgaagAfAfAfAfGfcag 3151 usAfsccgUfuCfuGfcuuUfuCfu aacgguasusu Ufcsusu ETD02191 3065 [ETL17]sgaagAfAfAfAfGfcag 3152 usAfsccgUfuCfugcUfuUfuCfu aacgguasusu Ufcsusu ETD02192 3066 [ETL17]sgaagAfAfAfAfGfcag 3153 usAfsccGfuUfcuGfcUfuUfuCf aacgguasusu uUfcsusu ETD02193 3067 [ETL17]sgaagAfAfAfAfGfcag 3154 usAfscCfguUfcuGfcUfuUfuCf aacgguasusu uUfcsusu ETD02194 3068 [ETL17]sgaagAfAfAfAfGfcag 3155 usAfscCfguUfcuGfcuuUfuCfu aacgguasusu Ufcsusu

TABLE 28 Example siRNA Base Sequences SEQ Sense Strand SEQ Antisense Strand siRNA ID Base Sequence ID Base Sequence Name NO: (5′ to 3′) NO: (5′ to 3′) ETD02075 2701 UCUACAAAGGUGAACUCAAUU 2883 UUGAGUUCACCUUUGUAGAUU ETD02179 2702 UCUACAAAGGUGAACUCAAUU 2884 UUGAGUUCACCUUUGUAGAUU ETD02180 2703 UCUACAAAGGUGAACUCAAUU 2885 UUGAGUUCACCUUUGUAGAUU ETD02181 2704 UCUACAAAGGUGAACUCAAUU 2886 UUGAGUUCACCUUUGUAGAUU ETD02182 2705 UCUACAAAGGUGAACUCAAUU 2887 UUGAGUUCACCUUUGUAGAUU ETD02183 2706 UCUACAAAGGUGAACUCAAUU 2888 UUGAGUUCACCUUUGUAGAUU ETD02184 2707 UCUACAAAGGUGAACUCAAUU 2889 UUGAGUUCACCUUUGUAGAUU ETD02185 2708 UCUACAAAGGUGAACUCAAUU 2890 UUGAGUUCACCUUUGUAGAUU ETD02186 2709 UCUACAAAGGUGAACUCAAUU 2891 UUGAGUUCACCUUUGUAGAUU ETD02077 2710 GAAGAAAAGCAGAACGGUAUU 2892 UACCGUUCUGCUUUUCUUCUU ETD02187 2711 GAAGAAAAGCAGAACGGUAUU 2893 UACCGUUCUGCUUUUCUUCUU ETD02188 2712 GAAGAAAAGCAGAACGGUAUU 2894 UACCGUUCUGCUUUUCUUCUU ETD02189 2713 GAAGAAAAGCAGAACGGUAUU 2895 UACCGUUCUGCUUUUCUUCUU ETD02190 2714 GAAGAAAAGCAGAACGGUAUU 2896 UACCGUUCUGCUUUUCUUCUU ETD02191 2715 GAAGAAAAGCAGAACGGUAUU 2897 UACCGUUCUGCUUUUCUUCUU ETD02192 2716 GAAGAAAAGCAGAACGGUAUU 2898 UACCGUUCUGCUUUUCUUCUU ETD02193 2717 GAAGAAAAGCAGAACGGUAUU 2899 UACCGUUCUGCUUUUCUUCUU ETD02194 2718 GAAGAAAAGCAGAACGGUAUU 2900 UACCGUUCUGCUUUUCUUCUU Antisense Strand SEQ Sense Strand Base SEQ Base Sequence siRNA ID Sequence (5′ to 3′), ID (5′ to 3′), without Name NO: without 3′ overhangs NO: 3′ overhangs ETD02075 2720 UCUACAAAGGUGAACUCAA 2902 UUGAGUUCACCUUUGUAGA ETD02179 2721 UCUACAAAGGUGAACUCAA 2903 UUGAGUUCACCUUUGUAGA ETD02180 2722 UCUACAAAGGUGAACUCAA 2904 UUGAGUUCACCUUUGUAGA ETD02181 2723 UCUACAAAGGUGAACUCAA 2905 UUGAGUUCACCUUUGUAGA ETD02182 2724 UCUACAAAGGUGAACUCAA 2906 UUGAGUUCACCUUUGUAGA ETD02183 2725 UCUACAAAGGUGAACUCAA 2907 UUGAGUUCACCUUUGUAGA ETD02184 2726 UCUACAAAGGUGAACUCAA 2908 UUGAGUUCACCUUUGUAGA ETD02185 2727 UCUACAAAGGUGAACUCAA 2909 UUGAGUUCACCUUUGUAGA ETD02186 2728 UCUACAAAGGUGAACUCAA 2910 UUGAGUUCACCUUUGUAGA ETD02077 2729 GAAGAAAAGCAGAACGGUA 2911 UACCGUUCUGCUUUUCUUC ETD02187 2730 GAAGAAAAGCAGAACGGUA 2912 UACCGUUCUGCUUUUCUUC ETD02188 2731 GAAGAAAAGCAGAACGGUA 2913 UACCGUUCUGCUUUUCUUC ETD02189 2732 GAAGAAAAGCAGAACGGUA 2914 UACCGUUCUGCUUUUCUUC ETD02190 2733 GAAGAAAAGCAGAACGGUA 2915 UACCGUUCUGCUUUUCUUC ETD02191 2734 GAAGAAAAGCAGAACGGUA 2916 UACCGUUCUGCUUUUCUUC ETD02192 2735 GAAGAAAAGCAGAACGGUA 2917 UACCGUUCUGCUUUUCUUC ETD02193 2736 GAAGAAAAGCAGAACGGUA 2918 UACCGUUCUGCUUUUCUUC ETD02194 2737 GAAGAAAAGCAGAACGGUA 2919 UACCGUUCUGCUUUUCUUC

TABLE 29 Relative MTRES1 mRNA Levels in Livers of Mice Dose Mean MTRES1 mRNA (Normalized Group n Treatment (ug) to Group 1, Day 14) 1 3 PBS 1 2 3 ETD02075 100 0.11 3 3 ETD02179 100 0.2 4 3 ETD02180 100 0.22 5 3 ETD02181 100 0.14 6 3 ETD02182 100 0.1 7 3 ETD02183 100 0.1 8 3 ETD02184 100 0.2 9 3 ETD02185 100 0.12 10 3 ETD02186 100 0.26 11 3 ETD02077 100 0.2 12 3 ETD02187 100 0.22 13 3 ETD02188 100 0.16 14 3 ETD02189 100 0.12 15 3 ETD02190 100 0.23 16 3 ETD02191 100 0.16 17 3 ETD02192 100 0.15 18 3 ETD02193 100 0.16 19 3 ETD02194 100 0.27

The activities of the siRNAs ETD02072, ETD02073, ETED02078 and ETD02080, which contain 2′deoxynucleotide, were compared to the activities of siRNAs in which the 2′deoxynucleotide was replaced with 2′F nucleotide. The siRNA sequences are shown in Table 30, where Nf is a 2′-fluoro-modified nucleoside, n is a 2′-O-methyl modified nucleoside, “d” is a deoxynucleoside, and “s” is a phosphorothioate linkage. All siRNAs contained the GalNAc ligand ETL17. Base sequences are shown in Table 31.

Six- to eight-week-old female mice (strain ICR, n=3) were given a subcutaneous injection on Day 0 of a single 100 μg dose of a GalNAc-conjugated siRNA or PBS as vehicle control.

Mice were euthanized on Day 14 after injection and a liver sample from each was collected and placed in RNAlater (ThermoFisher Catalog #AM7020) until processing. Total liver RNA was prepared by homogenizing the liver tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer's recommendations. Preparation of cDNA was performed using Quanta qScript cDNA SuperMix (VWR, Catalog #95048-500) according to the manufacturer's instructions. The relative levels of liver MTRES1 mRNA were assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for mouse MTRES1 (ThermoFisher, assay #Mm01229834_m1) and the mouse housekeeping gene PPIA (ThermoFisher, assay #Mm02342430_g1) and PerfeCTa® qPCR FastMix®, Low ROX™ (VWR, Catalog #101419-222). Data were normalized to the mean MTRES1 mRNA level in animals receiving PBS. Results are shown in Table 32. Replacement of 2′dN with a 2′F modification had differential effects on knockdown activity depending on the particular sequence of the siRNA. The mice receiving siRNA ETD02177, which possesses a 2′F at position 9 of the sense strand, showed a substantial increase in activity compared to the siRNA ETD02078 which had a with 2′dexoy at position 9 of the sense strand.

TABLE 30 Example siRNA Sequences Sense Antisense Strand Sense Strand Strand Antisense siRNA SEQ ID Sequence (5′-3′) SEQ ID Strand Sequence Name NO: with GalNAc moiety NO: (5′-3′) ETD02072 3069 [ETL17]succuGfgAfA 3156 usCfsaAfgUfaUfcGf fdTCfgauacuugasusu aUfuCfcAfgGfasusu ETD02175 3070 [ETL17]succuGfgAfA 3157 usCfsaAfgUfaUfcGf fUfcgauacuugasusu aUfuCfcAfgGfasusu ETD02073 3071 [ETL 17]sccugGfaAf 3158 usAfscAfaGfuAfuCf UfdCgauacuuguasusu gAfuUfcCfaGfgsusu ETD02176 3072 [ETL17]sccugGfaAfU 3159 usAfscAfaGfuAfuCf fCfgauacuuguasusu gAfuUfcCfaGfgsusu ETD02078 3073 [ETL17]saagaAfaAfG 3160 usCfsaCfcGfuUfcUf fdCagaacggugasusu gCfuUfuUfcUfususu ETD02177 3074 [ETL17]saagaAfaAfG 3161 usCfsaCfcGfuUfcUf fCfagaacggugasusu gCfuUfuUfcUfususu ETD02080 3075 [ETL17]scagaAfcGfG 3162 usCfscCfaCfuUfuCf fdTgaaagugggasusu aCfcGfuUfcUfgsusu ETD02178 3076 [ETL17]scagaAfcGfG 3163 usCfscCfaCfuUfuCf fUfgaaagugggasusu aCfcGfuUfcUfgsusu

TABLE 31 Example siRNA BASE Sequences SEQ Sense Strand SEQ Antisense Strand siRNA ID Base Sequence ID Base Sequence Name NO: (5′ to 3′) NO: (5′ to 3′) ETD02072 2739 UCCUGGAATCGAUACUUGAUU 2921 UCAAGUAUCGAUUCCAGGAUU ETD02175 2740 UCCUGGAAUCGAUACUUGAUU 2922 UCAAGUAUCGAUUCCAGGAUU ETD02073 2741 CCUGGAAUCGAUACUUGUAUU 2923 UACAAGUAUCGAUUCCAGGUU ETD02176 2742 CCUGGAAUCGAUACUUGUAUU 2924 UACAAGUAUCGAUUCCAGGUU ETD02078 2743 AAGAAAAGCAGAACGGUGAUU 2925 UCACCGUUCUGCUUUUCUUUU ETD02177 2744 AAGAAAAGCAGAACGGUGAUU 2926 UCACCGUUCUGCUUUUCUUUU ETD02080 2745 CAGAACGGTGAAAGUGGGAUU 2927 UCCCACUUUCACCGUUCUGUU ETD02178 2746 CAGAACGGUGAAAGUGGGAUU 2928 UCCCACUUUCACCGUUCUGUU Antisense Strand SEQ Sense Strand Base SEQ Base Sequence siRNA ID Sequence (5′ to 3′), ID (5′ to 3′), without Name NO: without 3′ overhangs NO: 3′ overhangs ETD02072 2748 UCCUGGAATCGAUACUUGA 2930 UCAAGUAUCGAUUCCAGGA ETD02175 2749 UCCUGGAAUCGAUACUUGA 2931 UCAAGUAUCGAUUCCAGGA ETD02073 2750 CCUGGAAUCGAUACUUGUA 2932 UACAAGUAUCGAUUCCAGG ETD02176 2751 CCUGGAAUCGAUACUUGUA 2933 UACAAGUAUCGAUUCCAGG ETD02078 2752 AAGAAAAGCAGAACGGUGA 2934 UCACCGUUCUGCUUUUCUU ETD02177 2753 AAGAAAAGCAGAACGGUGA 2935 UCACCGUUCUGCUUUUCUU ETD02080 2754 CAGAACGGTGAAAGUGGGA 2936 UCCCACUUUCACCGUUCUG ETD02178 2755 CAGAACGGUGAAAGUGGGA 2937 UCCCACUUUCACCGUUCUG

TABLE 32 Relative MTRES1 mRNA Levels in Livers of Mice Dose Mean MTRES1 mRNA (Normalized Group n Treatment (ug) to Group 1, Day 14) 1 3 PBS 1 2 3 ETD02072 100 0.3 3 3 ETD02175 100 0.49 4 3 ETD02073 100 1.22 5 3 ETD02176 100 0.92 6 3 ETD02078 100 0.53 7 3 ETD02177 100 0.09 8 3 ETD02080 100 1.05 9 3 ETD02178 100 1.5

Five additional siRNAs, ETD02349 through ETD02353, designed to be cross-reactive with at least human and mouse MTRES1 mRNA, were tested for activity in mice. The siRNAs contained the GalNAc ligand ETL17. The siRNA sequences are shown in Table 33, where Nf is a 2′-fluoro-modified nucleoside, n is a 2′-O-methyl modified nucleoside, “d” is a deoxynucleoside, and “s” is a phosphorothioate linkage. Base sequences are shown in Table 34.

Six- to eight-week-old female mice (strain ICR, n=3) were given a subcutaneous injection on Day 0 of a single 100 μg dose of a GalNAc-conjugated siRNA or PBS as vehicle control. Mice receiving with ETD02182 and ETD02189 were included as positive controls.

Mice were euthanized on Day 14 after injection and a liver sample from each was collected and placed in RNAlater (ThermoFisher Catalog #AM7020) until processing. Total liver RNA was prepared by homogenizing the liver tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer's recommendations. Preparation of cDNA was performed using Quanta qScript cDNA SuperMix (VWR, Catalog #95048-500) according to the manufacturer's instructions. The relative levels of liver MTRES1 mRNA were assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for mouse MTRES1 (ThermoFisher, assay #Mm01229834_m1) and the mouse housekeeping gene PPIA (ThermoFisher, assay #Mm02342430_g1) and PerfeCTa® qPCR FastMix®, Low ROX™ (VWR, Catalog #101419-222). Data were normalized to the mean MTRES1 mRNA level in animals receiving PBS. Results are shown in Table 35. Of the siRNAs ETD02349 through ETD02353, Mice receiving ETED02352 had the highest level of mean MTRES1 mRNA knockdown in the liver of the additional siRNAs.

TABLE 33 Example siRNA Sequences Sense Antisense Strand Sense Strand Strand Antisense siRNA SEQ ID Sequence (5′-3′) SEQ ID Strand Sequence Name NO: with GalNAc moiety NO: (5′-3′) ETD02182 3077 [ETL17]sucuacAfAfAfGfGfug 3164 usUfsgagUfuCfaCfcUfuUfgUf aacucaasusu aGfasusu ETD02189 3078 [ETL17]sgaagAfAfAfAfGfcag 3165 usAfsccgUfuCfuGfcUfuUfuCf aacgguasusu uUfcsusu ETD02349 3079 [ETL17]saucgaUfaCfUfuguauu 3166 usAfsaAfaAfuAfcAfaGfuAfu CfgAfususu ETD02350 3080 [ETL17]sagacUfcCfCfdAgGfg 3167 usUfsaAfaAfgCfcCfuGfgGfa GfuCfususu ETD02351 3081 [ETL17]sugcuUfuCfUfdAcAfa 3168 usUfscAfcCfuUfuGfuAfgAfa aggugaasusu AfgCfasusu ETD02352 3082 [ETL17]suacaAfaGfGfdTgAfa 3169 usCfscUfgAfgUfuCfaCfcUfu cucaggasusu UfgUfasusu ETD02353 3083 [ETL17]sagcaGfaAfcGfGfugaa 3170 usCfsaCfuUfuCfaCfcGfuUfc agugasusu UfgCfususu

TABLE 34 Example siRNA BASE Sequences Sense Strand Antisense Strand SiRNA SEQ ID Base Sequence SEQ ID Base Sequence Name NO: (5′ to 3′) NO: (5′ to 3′) ETD02182 2756 UCUACAAAGGUGAACUCAAUU 2938 UUGAGUUCACCUUUGUAGAUU ETD02189 2757 GAAGAAAAGCAGAACGGUAUU 2939 UACCGUUCUGCUUUUCUUCUU ETD02349 2758 AUCGAUACUUGUAUUUUUAUU 2940 UAAAAAUACAAGUAUCGAUUU ETD02350 2759 AGACUCCCAGGGCUUUUAAUU 2941 UUAAAAGCCCUGGGAGUCUUU ETD02351 2760 UGCUUUCUACAAAGGUGAAUU 2942 UUCACCUUUGUAGAAAGCAUU ETD02352 2761 UACAAAGGTGAACUCAGGAUU 2943 UCCUGAGUUCACCUUUGUAUU ETD02353 2762 AGCAGAACGGUGAAAGUGAUU 2944 UCACUUUCACCGUUCUGCUUU Sense Strand Base Sense Strand Base siRNA SEQ ID Sequence (5′ to 3′), SEQ ID Sequence (5′ to 3′), Name NO: without 3′ overhangs NO: without 3′ overhangs ETD02182 2764 UCUACAAAGGUGAACUCAA 2946 UUGAGUUCACCUUUGUAGA ETD02189 2765 GAAGAAAAGCAGAACGGUA 2947 UACCGUUCUGCUUUUCUUC ETD02349 2766 AUCGAUACUUGUAUUUUUA 2948 UAAAAAUACAAGUAUCGAU ETD02350 2767 AGACUCCCAGGGCUUUUAA 2949 UUAAAAGCCCUGGGAGUCU ETD02351 2768 UGCUUUCUACAAAGGUGAA 2950 UUCACCUUUGUAGAAAGCA ETD02352 2769 UACAAAGGTGAACUCAGGA 2951 UCCUGAGUUCACCUUUGUA ETD02353 2770 AGCAGAACGGUGAAAGUGA 2952 UCACUUUCACCGUUCUGCU

TABLE 35 Relative MTRES1 mRNA Levels in Livers of Mice Dose Mean MTRES1 mRNA (Normalized Group n Treatment (ug) to Group 1, Day 14) 1 3 PBS 1 2 3 ETD02182 100 0.04 3 3 ETD02189 100 0.05 4 3 ETD02349 100 1.16 5 3 ETD02350 100 0.81 6 3 ETD02351 100 0.66 7 3 ETD02352 100 0.17 8 3 ETD02353 100 0.66

ETD02075 and ETD02077 and siRNAs of the same base sequences containing alternative modifications were tested for activity in mice following transfection with an adeno-associated viral vector expressing human MTRES1. The siRNAs were attached to the GalNAc ligand ETL17. The siRNA sequences are shown in Table 36, where “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate linkage. Base sequences are shown in Table 37.

Six- to eight-week-old female mice (C57Bl/6) were injected with 5 μL of a recombinant adeno-associated virus 8 (AAV8) vector (1.4×10E13 genome copies/mL) by the retroorbital route on Day-14. The recombinant AAV8 contained the open reading frame and the majority of the 3′UTR of the human MTRES1 sequence (NM_016487.5) under the control of the human thyroxine binding globulin promoter in an AAV2 backbone packaged in AAV8 capsid (AAV8-TBG-h-MTRES1). On Day 0, infected mice (n=8) were given a subcutaneous injection of a single 100 μg dose of a GalNAc-conjugated siRNA or PBS as vehicle control.

Mice were euthanized on Day 14 after subcutaneous injection and a liver sample from each was collected and placed in RNAlater (ThermoFisher Catalog #AM7020) until processing. Total liver RNA was prepared by homogenizing the liver tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer's recommendations. Preparation of cDNA was performed using Quanta qScript cDNA SuperMix (VWR, Catalog #95048-500) according to the manufacturer's instructions. The relative levels of liver MTRES1 mRNA were assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for human MTRES1 (ThermoFisher, assay #Hs01568158_g1) and the mouse housekeeping gene PPIA (ThermoFisher, assay #Mm02342430_g1) and PerfeCTa® qPCR FastMix®, Low ROX™ (VWR, Catalog #101419-222). Data were normalized to the mean MTRES1 mRNA level in animals receiving PBS. Results are shown in Table 38. Mice injected with ETD02077, ETD02192, ETD02075, ETD02182, ETD02183 and ETD02185 had reductions in mean liver MTRES1 mRNA relative to mice receiving PBS.

TABLE 36 Example siRNA Sequences Sense Antisense Strand Sense Strand Strand Antisense Strand siRNA SEQ ID Sequence (5′-3′) SEQ ID Sequence Name NO: with GalNAc moiety NO: (5′-3′) ETD02077 3084 [ETL17]sgaagAfAfAfAfGfcag 3171 usAfscCfgUfuCfuGfcUfuUfu aacgguasusu CfuUfcsusu ETD02189 3085 [ETL17]sgaagAfAfAfAfGfcag 3172 usAfsccgUfuCfuGfcUfuUfuCf aacgguasusu uUfcsusu ETD02192 3086 [ETL17]sgaagAfAfAfAfGfcag 3174 usAfsccGfuUfcuGfcUfuUfuCf aacgguasusu uUfcsusu ETD02075 3087 [ETL17]sucuacAfAfAfGfGfug 3175 usUfsgAfgUfuCfaCfcUfuUfg aacucaasusu UfaGfasusu ETD02182 3088 [ETL17]sucuacAfAfAfGfGfug 3176 usUfsgagUfuCfaCfcUfuUfgUf aacucaasusu aGfasusu ETD02183 3089 [ETL17]sucuacAfAfAfGfGfug 3177 usUfsgaGfuUfcaCfcUfuUfgUf aacucaasusu aGfasusu ETD02185 3090 [ETL17]sucuacAfAfAfGfGfug 3178 usUfsgAfguUfcAfccuuUfgUfa aacucaasusu Gfasusu

TABLE 37 Example siRNA BASE Sequences Sense Strand Antisense Strand siRNA SEQ ID Base Sequence SEQ ID Base Sequence Name NO: (5′ to 3′) NO: (5′ to 3′) ETD02077 2771 GAAGAAAAGCAGAACGGUAUU 2953 UACCGUUCUGCUUUUCUUCUU ETD02189 2772 GAAGAAAAGCAGAACGGUAUU 2954 UACCGUUCUGCUUUUCUUCUU ETD02192 2773 GAAGAAAAGCAGAACGGUAUU 2955 UACCGUUCUGCUUUUCUUCUU ETD02075 2774 UCUACAAAGGUGAACUCAAUU 2956 UUGAGUUCACCUUUGUAGAUU ETD02182 2775 UCUACAAAGGUGAACUCAAUU 2957 UUGAGUUCACCUUUGUAGAUU ETD02183 2776 UCUACAAAGGUGAACUCAAUU 2958 UUGAGUUCACCUUUGUAGAUU ETD02185 2777 UCUACAAAGGUGAACUCAAUU 2959 UUGAGUUCACCUUUGUAGAUU Sense Strand Base Sense Strand Base siRNA SEQ ID Sequence (5′ to 3′), SEQ ID Sequence (5′ to 3′), name NO: without 3′ overhangs NO: without 3′ overhangs ETD02077 2779 GAAGAAAAGCAGAACGGUA 2961 UACCGUUCUGCUUUUCUUC ETD02189 2780 GAAGAAAAGCAGAACGGUA 2962 UACCGUUCUGCUUUUCUUC ETD02192 2781 GAAGAAAAGCAGAACGGUA 2963 UACCGUUCUGCUUUUCUUC ETD02075 2782 UCUACAAAGGUGAACUCAA 2964 UUGAGUUCACCUUUGUAGA ETD02182 2783 UCUACAAAGGUGAACUCAA 2965 UUGAGUUCACCUUUGUAGA ETD02183 2784 UCUACAAAGGUGAACUCAA 2966 UUGAGUUCACCUUUGUAGA ETD02185 2785 UCUACAAAGGUGAACUCAA 2967 UUGAGUUCACCUUUGUAGA

TABLE 38 Relative MTRES1 mRNA Levels in Livers of Mice Dose Mean MTRES1 mRNA (Normalized Group n Treatment (ug) to Group 1, Day 14) 1 8 PBS 1 2 8 ETD02077 100 0.72 3 8 ETD02189 100 1.38 4 8 ETD02192 100 0.62 5 8 ETD02075 100 0.34 6 8 ETD02182 100 0.08 7 8 ETD02183 100 0.44 8 8 ETD02185 100 0.21

Additional siRNAs targeting human MTRES1 mRNA and cross-reactive with at least cynomolgus monkey MTRES1 mRNA will be tested for activity in mice following transfection with an adeno-associated viral vector. The siRNAs are conjugated to the GalNAc ligand ETL17. The siRNA sequences are shown in Tables 39 and 40, where “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate linkage.

Six- to eight-week-old female mice (C57Bl/6) will be injected with 5 μL of a recombinant adeno-associated virus 8 (AAV8) vector (1.4×10E13 genome copies/mL) by the retroorbital route on Day-14. The recombinant AAV8 contained the open reading frame and the majority of the 3′UTR of the human MTRES1 sequence (NM_016487.5) under the control of the human thyroxine binding globulin promoter in an AAV2 backbone packaged in AAV8 capsid (AAV8-TBG-h-MTRES1). On Day 0, infected mice (n=8) will be given a subcutaneous injection of a single 100 μg dose of a GalNAc-conjugated siRNA or PBS as vehicle control.

Mice will be euthanized on Day 14 after subcutaneous injection and a liver sample from each will be collected and placed in RNAlater (ThermoFisher Catalog #AM7020) until processing. Total liver RNA will be prepared by homogenizing the liver tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the lysate will be purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer's recommendations. Preparation of cDNA will be performed using Quanta qScript cDNA SuperMix (VWR, Catalog #95048-500) according to the manufacturer's instructions. The relative levels of liver MTRES1 mRNA will be assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for human MTRES1 (ThermoFisher, assay #Hs01568158_g1) and the mouse housekeeping gene PPIA (ThermoFisher, assay #Mm02342430_g1) and PerfeCTaR qPCR FastMix®, Low ROX™ (VWR, Catalog #101419-222). Data will be normalized to the mean MTRES1 mRNA level in animals receiving PBS.

TABLE 39 Example siRNA Sequences Sense Antisense Strand Sense Strand Strand siRNA SEQ ID Sequence (5′-3′) SEQ ID Antisense Strand Sequence Name NO: with GalNAc moiety NO: (5′-3′) ETD02354 3091 [ETL17]suggcuAfGfuGfuuaaau 3179 usGfscAfaUfuUfaAfcAfcUfa ugcasusu GfcCfasusu ETD02355 3092 [ETL17]sggcuagUfgUfUfaaauu 3180 usAfsgCfaAfuUfuAfaCfaCfu gcuasusu AfgCfcsusu ETD02356 3093 [ETL17]sgcuagUfgUfUfaaauug 3181 usAfsaGfcAfaUfuUfaAfcAfc cuuasusu UfaGfcsusu ETD02357 3094 [ETL17]scggugUfUfUfUfaagaa 3182 usGfsgCfuUfuCfuUfaAfaAfc agccasusu AfcCfgsusu ETD02358 3095 [ETL17]sguacUfUfCfCfUfggaa 3183 usAfsuCfgAfuUfcCfaGfgAfa ucgauasusu GfuAfcsusu ETD02359 3096 [ETL17]scaaguuAfcGfuGfcacc 3184 usUfsuUfgGfuGfcAfcGfuAfa aaaasusu CfuUfgsusu ETD02360 3097 [ETL17]saaguUfaCfgUfgCfacc 3185 usAfsuUfuGfgUfgCfaCfgUfa aaauasusu AfcUfususu ETD02361 3098 [ETL17]sguuaCfgUfgCfaCfcaa 3186 usUfsaAfuUfuGfgUfgCfaCfg UfaAfcsusu ETD02362 3099 [ETL17]sauauUfUfUfCfUfcacu 3187 usGfsuCfuCfaGfuGfaGfaAfa gagacasusu AfuAfususu ETD02363 3100 [ETL17]sgucuAfcAfAfAfAfuc 3188 usUfsuAfgUfaGfaUfuUfuGfu uacuaaasusu AfgAfcsusu ETD02364 3101 [ETL17]sagucUfUfUfUfCfggu 3189 usCfsaUfcAfuAfcCfgAfaAfa augaugasusu GfaCfususu ETD02365 3102 [ETL17]sggcuAfgAfuAfuuggg 3190 usUfsuCfuCfcCfaAfuAfuCfu agaaasusu AfgCfcsusu ETD02366 3103 [ETL17]sagauAfuuGfGfGfAfg 3191 usUfsuGfuUfuCfuCfcCfaAfu aaacaaasusu AfuCfususu ETD02367 3104 [ETL17]sgauacAfuuGfGfaucuu 3192 usGfsaGfaAfgAfuCfcAfaUfg cucasusu UfaUfcsusu ETD02368 3105 [ETL17]sucuuCfuCfaUfUfggag 3193 usUfscCfuCfuCfcAfaUfgAfg aggaasusu AfaGfasusu ETD02369 3106 [ETL17]scucauuGfGfAfGfAfg 3194 usUfsuUfaUfcCfuCfuCfcAfa gauaaaasusu UfgAfgsusu ETD02370 3107 [ETL17]sggauAfaAfGfAfAfgc 3195 usGfsuUfcCfuGfcUfuCfuUfu aggaacasusu AfuCfcsusu ETD02371 3108 [ETL17]sagagaCfagUfUfaugcg 3196 usAfsuCfcGfcAfuAfaCfuGfu gauasusu CfuCfususu ETD02372 3109 [ETL17]sagacAfGfuuAfuGfcg 3197 usGfsaAfuCfcGfcAfuAfaCfu gauucasusu GfuCfususu ETD02373 3110 [ETL17]scaguUfaUfgCfggauuc 3198 usAfsgAfgAfaUfcCfgCfaUfa ucuasusu AfcUfgsusu ETD02374 3111 [ETL17]suuauGfcGfgAfuucucu 3199 usUfscAfaGfaGfaAfuCfcGfc ugaasusu AfuAfasusu ETD02375 3112 [ETL17]sgcggaUfUfCfUfcUfu 3200 usUfsuUfuUfcAfaGfaGfaAfu gaaaaaasusu CfcGfcsusu ETD02376 3113 [ETL17]sagugAfaAfaAfuAfcag 3201 usCfsaCfuCfuGfuAfuUfuUfu agugasusu CfaCfususu ETD02377 3114 [ETL17]sggcgGfuGfgAfaAfag 3202 usUfsuAfaAfcUfuUfuCfcAfc uuuaaasusu CfgCfcsusu ETD02378 3115 [TL17]sgcgguGfGfAfAfaAfg 3203 usUfsuUfaAfaCfuUfuUfcCfa uuuaaaasusu CfcGfcsusu ETD02379 3116 [ETL17]sguuuAfaAfGfdTuGfc 3204 usUfscUfuAfgGfcAfaCfuUfu cuaagaasusu AfaAfcsusu ETD02380 3117 [ETL17]sagcugCfUfuUfcUfagu 3205 usUfsaCfcAfcUfaGfaAfaGfc gguaasusu AfgCfususu

TABLE 40 Example siRNA BASE Sequences Sense Strand Antisense Strand siRNA SEQ ID Base Sequence SEQ ID Base Sequence Name NO: (5′ to 3′) NO: (5′ to 3′) ETD02354 2786 UGGCUAGUGUUAAAUUGCAUU 2968 UGCAAUUUAACACUAGCCAUU ETD02355 2787 GGCUAGUGUUAAAUUGCUAUU 2969 UAGCAAUUUAACACUAGCCUU ETD02356 2788 GCUAGUGUUAAAUUGCUUAUU 2970 UAAGCAAUUUAACACUAGCUU ETD02357 2789 CGGUGUUUUAAGAAAGCCAUU 2971 UGGCUUUCUUAAAACACCGUU ETD02358 2790 GUACUUCCUGGAAUCGAUAUU 2972 UAUCGAUUCCAGGAAGUACUU ETD02359 2791 CAAGUUACGUGCACCAAAAUU 2973 UUUUGGUGCACGUAACUUGUU ETD02360 2792 AAGUUACGUGCACCAAAUAUU 2974 UAUUUGGUGCACGUAACUUUU ETD02361 2793 GUUACGUGCACCAAAUUAAUU 2975 UUAAUUUGGUGCACGUAACUU ETD02362 2794 AUAUUUUCUCACUGAGACAUU 2976 UGUCUCAGUGAGAAAAUAUUU ETD02363 2795 GUCUACAAAAUCUACUAAAUU 2977 UUUAGUAGAUUUUGUAGACUU ETD02364 2796 AGUCUUUUCGGUAUGAUGAUU 2978 UCAUCAUACCGAAAAGACUUU ETD02365 2797 GGCUAGAUAUUGGGAGAAAUU 2979 UUUCUCCCAAUAUCUAGCCUU ETD02366 2798 AGAUAUUGGGAGAAACAAAUU 2980 UUUGUUUCUCCCAAUAUCUUU ETD02367 2799 GAUACAUUGGAUCUUCUCAUU 2981 UGAGAAGAUCCAAUGUAUCUU ETD02368 2800 UCUUCUCAUUGGAGAGGAAUU 2982 UUCCUCUCCAAUGAGAAGAUU ETD02369 2801 CUCAUUGGAGAGGAUAAAAUU 2983 UUUUAUCCUCUCCAAUGAGUU ETD02370 2802 GGAUAAAGAAGCAGGAACAUU 2984 UGUUCCUGCUUCUUUAUCCUU ETD02371 2803 AGAGACAGUUAUGCGGAUAUU 2985 UAUCCGCAUAACUGUCUCUUU ETD02372 2804 AGACAGUUAUGCGGAUUCAUU 2986 UGAAUCCGCAUAACUGUCUUU ETD02373 2805 CAGUUAUGCGGAUUCUCUAUU 2987 UAGAGAAUCCGCAUAACUGUU ETD02374 2806 UUAUGCGGAUUCUCUUGAAUU 2988 UUCAAGAGAAUCCGCAUAAUU ETD02375 2807 GCGGAUUCUCUUGAAAAAAUU 2989 UUUUUUCAAGAGAAUCCGCUU ETD02376 2808 AGUGAAAAAUACAGAGUGAUU 2990 UCACUCUGUAUUUUUCACUUU ETD02377 2809 GGCGGUGGAAAAGUUUAAAUU 2991 UUUAAACUUUUCCACCGCCUU ETD02378 2810 GCGGUGGAAAAGUUUAAAAUU 2992 UUUUAAACUUUUCCACCGCUU ETD02379 2811 GUUUAAAGTUGCCUAAGAAUU 2993 UUCUUAGGCAACUUUAAACUU ETD02380 2812 AGCUGCUUUCUAGUGGUAAUU 2994 UUACCACUAGAAAGCAGCUUU Sense Strand Base Sense Strand Base SiRNA SEQ ID Sequence (5′ to 3′), SEQ ID Sequence (5′ to 3′), Name NO: without 3′ overhangs NO: without 3′ overhangs ETD02354 2814 UGGCUAGUGUUAAAUUGCA 2996 UGCAAUUUAACACUAGCCA ETD02355 2815 GGCUAGUGUUAAAUUGCUA 2997 UAGCAAUUUAACACUAGCC ETD02356 2816 GCUAGUGUUAAAUUGCUUA 2998 UAAGCAAUUUAACACUAGC ETD02357 2817 CGGUGUUUUAAGAAAGCCA 2999 UGGCUUUCUUAAAACACCG ETD02358 2818 GUACUUCCUGGAAUCGAUA 3000 UAUCGAUUCCAGGAAGUAC ETD02359 2819 CAAGUUACGUGCACCAAAA 3001 UUUUGGUGCACGUAACUUG ETD02360 2820 AAGUUACGUGCACCAAAUA 3002 UAUUUGGUGCACGUAACUU ETD02361 2821 GUUACGUGCACCAAAUUAA 3003 UUAAUUUGGUGCACGUAAC ETD02362 2822 AUAUUUUCUCACUGAGACA 3004 UGUCUCAGUGAGAAAAUAU ETD02363 2823 GUCUACAAAAUCUACUAAA 3005 UUUAGUAGAUUUUGUAGAC ETD02364 2824 AGUCUUUUCGGUAUGAUGA 3006 UCAUCAUACCGAAAAGACU ETD02365 2825 GGCUAGAUAUUGGGAGAAA 3007 UUUCUCCCAAUAUCUAGCC ETD02366 2826 AGAUAUUGGGAGAAACAAA 3008 UUUGUUUCUCCCAAUAUCU ETD02367 2827 GAUACAUUGGAUCUUCUCA 3009 UGAGAAGAUCCAAUGUAUC ETD02368 2828 UCUUCUCAUUGGAGAGGAA 3010 UUCCUCUCCAAUGAGAAGA ETD02369 2829 CUCAUUGGAGAGGAUAAAA 3011 UUUUAUCCUCUCCAAUGAG ETD02370 2830 GGAUAAAGAAGCAGGAACA 3012 UGUUCCUGCUUCUUUAUCC ETD02371 2831 AGAGACAGUUAUGCGGAUA 3013 UAUCCGCAUAACUGUCUCU ETD02372 2832 AGACAGUUAUGCGGAUUCA 3014 UGAAUCCGCAUAACUGUCU ETD02373 2833 CAGUUAUGCGGAUUCUCUA 3015 UAGAGAAUCCGCAUAACUG ETD02374 2834 UUAUGCGGAUUCUCUUGAA 3016 UUCAAGAGAAUCCGCAUAA ETD02375 2835 GCGGAUUCUCUUGAAAAAA 3017 UUUUUUCAAGAGAAUCCGC ETD02376 2836 AGUGAAAAAUACAGAGUGA 3018 UCACUCUGUAUUUUUCACU ETD02377 2837 GGCGGUGGAAAAGUUUAAA 3019 UUUAAACUUUUCCACCGCC ETD02378 2838 GCGGUGGAAAAGUUUAAAA 3020 UUUUAAACUUUUCCACCGC ETD02379 2839 GUUUAAAGTUGCCUAAGAA 3021 UUCUUAGGCAACUUUAAAC ETD02380 2840 AGCUGCUUUCUAGUGGUAA 3022 UUACCACUAGAAAGCAGCU

The base sequence of ETD01955 was synthesized with alternative modification patterns and then these were tested for activity in mice. The siRNA sequences are shown in Table 41, where Nf is a 2′-fluoro-modified nucleoside, n is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate linkage. All siRNAs were conjugated to the GalNAc ligand ETL17. Base sequences are shown in Table 42.

Six- to eight-week-old female mice (strain ICR, n=3) were given a subcutaneous injection on Day 0 of a single 100 μg dose of a GalNAc-conjugated siRNA or PBS as vehicle control.

Mice were euthanized on Day 14 after injection and a liver sample from each was collected and placed in RNAlater (ThermoFisher Catalog #AM7020) until processing. Total liver RNA was prepared by homogenizing the liver tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer's recommendations. Preparation of cDNA was performed using Quanta qScript cDNA SuperMix (VWR, Catalog #95048-500) according to the manufacturer's instructions. The relative levels of liver MTRES1 mRNA were assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for mouse MTRES1 (ThermoFisher, assay #Mm01229834_m1) and the mouse housekeeping gene PPIA (ThermoFisher, assay #Mm02342430_g1) and PerfeCTaR qPCR FastMix®, Low ROX™ (VWR, Catalog #101419-222). Data were normalized to the mean MTRES1 mRNA level in animals receiving PBS. Results are shown in Table 43. Of the alternatively modified versions of ETD01955, mice receiving ETD02106 had the highest level of mean MTRES1 mRNA knockdown in the liver.

TABLE 41 Example siRNA Sequences Sense Antisense Strand Sense Strand Strand Antisense siRNA SEQ ID Sequence (5′-3′) SEQ ID Strand Sequence Name NO: with GalNAc moiety NO: (5′-3′) ETD02105 3118 [ETL17]scuuccuGfGf 3206 usAfsguaUfcGfaUfu AfAfucgauacuasusu CfcAfgGfaAfgsusu ETD02106 3119 [ETL17]scuuccuGfGf 3207 usAfsguauCfgaUfuC AfAfucgauacuasusu fcAfgGfaAfgsusu ETD02107 3120 [ETL17]scuuccuGfGf 3208 usAfsguauCfgAfuuC AfAfucgauacuasusu fcAfgGfaAfgsusu ETD02108 3121 [ETL17]scuuccuGfGf 3209 usAfsguauCfgAfuuc AfAfucgauacuasusu cAfgGfaAfgsusu ETD02109 3122 [ETL17]scuuccuGfG 3210 usAfsguAfuCfgAfuu fAfAfucgauacuasusu ccAfgGfaAfgsusu ETD02110 3123 [ETL17]scuuccuGfGf 3211 usAfsgUfaUfcGfauu AfAfucgauacuasusu ccAfgGfaAfgsusu ETD02111 3124 [ETL17]scuuccuGfGf 3212 usAfsguaUfcGfaUfu AfAfucgauacuasusu ccAfgGfaAfgsusu

TABLE 42 Example siRNA BASE Sequences Sense Strand Antisense Strand siRNA SEQ ID Base Sequence SEQ ID Base Sequence Name NO: (5′ to 3′) NO: (5′ to 3′) ETD02105 2841 CUUCCUGGAAUCGAUACUAUU 3023 UAGUAUCGAUUCCAGGAAGUU ETD02106 2842 CUUCCUGGAAUCGAUACUAUU 3024 UAGUAUCGAUUCCAGGAAGUU ETD02107 2843 CUUCCUGGAAUCGAUACUAUU 3025 UAGUAUCGAUUCCAGGAAGUU ETD02108 2844 CUUCCUGGAAUCGAUACUAUU 3026 UAGUAUCGAUUCCAGGAAGUU ETD02109 2845 CUUCCUGGAAUCGAUACUAUU 3027 UAGUAUCGAUUCCAGGAAGUU ETD02110 2846 CUUCCUGGAAUCGAUACUAUU 3028 UAGUAUCGAUUCCAGGAAGUU ETD02111 2847 CUUCCUGGAAUCGAUACUAUU 3029 UAGUAUCGAUUCCAGGAAGUU Sense Strand Base Sense Strand Base siRNA SEQ ID Sequence (5′ to 3′), SEQ ID Sequence (5′ to 3′), Name NO: without 3′ overhangs NO: without 3′ overhangs ETD02105 2849 CUUCCUGGAAUCGAUACUA 3031 UAGUAUCGAUUCCAGGAAG ETD02106 2850 CUUCCUGGAAUCGAUACUA 3032 UAGUAUCGAUUCCAGGAAG ETD02107 2851 CUUCCUGGAAUCGAUACUA 3033 UAGUAUCGAUUCCAGGAAG ETD02108 2852 CUUCCUGGAAUCGAUACUA 3034 UAGUAUCGAUUCCAGGAAG ETD02109 2853 CUUCCUGGAAUCGAUACUA 3035 UAGUAUCGAUUCCAGGAAG ETD02110 2854 CUUCCUGGAAUCGAUACUA 3036 UAGUAUCGAUUCCAGGAAG ETD02111 2855 CUUCCUGGAAUCGAUACUA 3037 UAGUAUCGAUUCCAGGAAG

TABLE 43 Relative MTRES1 mRNA Levels in Livers of Mice Dose Mean MTRES1 mRNA (Normalized Group n Treatment (ug) to Group 1, Day 14) 1 4 PBS 1 2 4 ETD02105 100 0.23 3 4 ETD02106 100 0.18 4 4 ETD02107 100 0.22 5 4 ETD02108 100 0.29 6 4 ETD02109 100 0.29 7 4 ETD02110 100 0.5 8 4 ETD02111 100 0.5

2 2 2 2 Synthesis of N-(4-hydroxyphenethyl) palmitamide (5): 12.82 grams of 1 (palmitic acid) were weighed out and dissolved in 450 mL of CHCl. 16.3 mL di-isopropyl ethyl amine (DIEA) was added to the solution of 1. Afterwards, 12.88 mL of 2 (perfluorophenyl 2,2,2-trifluoroaceate, “PFP”) was added dropwise, and the reaction was stirred for 10 minutes after addition was completed. To the solution of PFP activated acid, 8.26 grams of 4 (4-(2-aminoethyl) phenol) was added via an addition funnel, and the addition funnel was rinsed with 50 mL CHCl. The reaction was placed under Argon and stirred overnight. After stirring overnight 5 formed a precipitate. The precipitate was collected via filtration and washed with 75 mL MTBE, previously chilled to −20° C. The white to off-white solid was dried overnight under high vacuum. The product was used in the next step without further purification.

3 2 4 Synthesis of ETL20 phosphoramidite (6): 100 mL anhydrous ethyl acetate was added to N-(4-hydroxyphenethyl) palmitamide 5 (5.2 grams), followed by addition of 250 mg 3-Angstrom molecular sieves. The mixture was stirred for 1 hr. The mixture was heated at 50° C. to obtain a clear solution. 7.3 mL of DIEA was added, and mixture was placed into an ice bath, and the solution became cloudy. 3-((chloro(diisopropylamino)phosphaneyl)oxy) propanenitrile (3.5 mL) was slowly added to the cloudy solution. After addition was completed, the reaction mixture was removed from the ice bath and stirred at room temperature overnight under Ar. The reaction mixture was then diluted with ethyl acetate (200 mL), washed with saturated NaHCOsolution (2×50 mL) followed by brine (50 mL). The solution was dried over NaSO, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography and eluted with 5-30% ethyl acetate in hexanes containing 2% triethylamine.

14 12 12 14 ETL18 (C) and ETL19 (C) phosphoramidites were synthesized using the procedure to generate ETL20 phosphoramidite with hydroxylbenzylamine and lauryl (C) or myristic (C) acids.

−1 siRNA sequences are depicted in Table 44, where Nf is a 2′-fluoro-modified nucleoside, n is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate linkage. ETL3 is stearyl coupled to 5′ of sense strand using stearyl phosphoramidite (Glen Research, 10-1979-90), and 5VP is vinyl phosphonate at 5′ end of antisense strand using 5′-POM-vinyl phosphonate, 2′-OMe-U CE-Phosphoramidite (Biosearch Technologies, 2579). Mice were induced to anesthetic states in an induction chamber with 1.2% isoflurane vaporized by oxygen of 1.0 L/min and then transferred and fixed to a stereotaxic frame while keeping anesthetized by 0.8% isoflurane through a mask. Skull was exposed and single intracerebroventricular injections (5 μl, artificial cerebrospinal fluid as vehicle) were performed at 500 nl minafter needle placement at the following coordinates from bregma: −0.2 mm anterior-posterior, 0.8 mm mediolateral and −2.5 mm dorsoventral using a Standard U-Frame Stereotaxic Instrument for Mouse (Harvard Apparatus 75-1808) and a Stereotaxic Anesthesia Adapters with Anesthesia Masks (Harvard Apparatus 75-1856).

TABLE 44 siRNA duplexes SEQ SEQ ID Entity # Target ID NO Sense Strand NO Antisense Strand ETD01917 MTRES1 3238 [ETL3]cuAfcAfaAfgGfuGfa 2468 usCfsugaGfuUfcaccuUfuGf AfcucAfgAfsusu uagsusu ETD02209 MTRES1 3239 [ELT20]cuAfcAfaAfgGfuGf 2468 usCfsugaGfuUfcaccuUfuGf aAfcucAfgAfsusu uagsusu ETD02137 MTRES1 3239 [ELT20]cuAfcAfaAfgGfuGf 3243 5VPusCfsugaGfuUfcaccuU aAfcucAfgAfsusu fuGfuagsusu ETD02210 MTRES1 3241 [ETL20]ucuacAfAfAfGfGfu 3244 5VPusUfsgAfgUfuCfaCfc gaacucaasusu UfuUfgUfaGfasusu ETD02211 MTRES1 3242 [ETL20]gaagAfAfAfAfGfca 3245 5VPusAfscCfgUfuCfuGfc gaacgguasusu UfuUfuCfuUfcsusu ETD02273 MTRES1 3241 [ETL20]ucuacAfAfAfGfGfu 3246 5VPusUfsgagUfuCfaCfcUf gaacucaasusu uUfgUfaGfasusu ETD02274 MTRES1 3241 [ETL20]ucuacAfAfAfGfGfu 3247 5VPusUfsgaGfuUfcaCfcUf gaacucaasusu uUfgUfaGfasusu ETD02275 MTRES1 3242 [ETL20]gaagAfAfAfAfGfca 3248 5VPusAfsccgUfuCfuGfcUf gaacgguasusu uUfuCfuUfcsusu ETD02276 MTRES1 3241 [ETL20]ucuacAfAfAfGfGfu 3249 5VPusUfsgAfguUfcAfccuu gaacucaasusu UfgUfaGfasusu ETD02319 MTRES1 3242 [ETL20]gaagAfAfAfAfGfca 3250 5VPusAfsccGfuUfcuGfcUf gaacgguasusu uUfuCfuUfcsusu

Mice were euthanized on day 14 or 28 post-injection. Brains from each animal were harvested and dissected into right and left hemispheres.

Total RNA was extracted from homogenized tissue and reverse transcribed to cDNA using a First-Strand III cDNA Synthesis kit. Normalized cDNA quantification was carried out by real-time TaqMan PCR using fluorescently labeled TaqMan assays for mouse MTRES1 (ThermoFisher, assay #Mm01229834_m1) and the mouse housekeeping gene PPIA (ThermoFisher, assay #Mm02342430_g1). Reactions were carried out in 20 μL aliquots using TaqMan Universal PCR Master Mix No AmpErase UNG ran on an ABI Prism 7500 Fast Real-Time PCR System Sequence Detection System and analyzed by the 7500 System software. Relative Quantification (RQ) values between treated and untreated samples are calculated by the formula 2-ΔΔCT, where CT is the cycle at threshold (automatic measurement), ΔCT is CT of the assayed gene (MTRES1) minus CT of the endogenous control (PPIA), and ΔΔCT is the ΔCT of the normalized assayed gene in the treated sample minus the ΔCT of the same gene in the untreated one (calibrator). Results are depicted in Tables 45-48.

TABLE 45 Relative MTRES1 mRNA Levels in Brains of Mice siRNA Average mRNA relative to no treatment control animals 25 μg dose ETD01917 0.9 ETD02209 0.44 10 μg dose ETD01917 0.45 ETD02209 0.22

TABLE 46 Relative MTRES1 mRNA Levels in Brains of Mice 14- and 28-Days Post-Injection Average mRNA relative to no siRNA treatment control animals 14 days post injection ETD02209 (100 μg) 0.2 ETD02137 (100 μg) 0.01 28 days post injection ETD02209 (100 μg) 0.04 ETD02137 (100 μg) 0.03

TABLE 47 Relative MTRES1 mRNA Levels in Brains of Mice 14 Days Post-Injection Average mRNA relative to no siRNA treatment control animals ETD02210 (100 μg) 0.05 ETD02211 (100 μg) 0.02

TABLE 48 Relative MTRES1 mRNA Levels in Brains of Mice 14 Days Post-Injection Average mRNA relative to no siRNA treatment control animals ETD02210 (50 μg) 0.04 ETD02211 (50 μg) 0.38 ETD02273 (50 μg) 0.03 ETD02274 (50 μg) 0.22 ETD02275 (50 μg) 0.21 ETD02276_(50 μg) 0.19 ETD02319_(50 μg) 0.31

Additional siRNAs targeting human MTRES1 mRNA and cross-reactive with at least cynomolgus monkey MTRES1 mRNA were tested for activity in mice following transfection with an adeno-associated viral vector. The siRNAs are conjugated to the GalNAc ligand ETL17. The siRNA sequences are shown in Tables 49 and 50, where “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate linkage.

Six- to eight-week-old female mice (C57Bl/6) were injected with 5 μL of a recombinant adeno-associated virus 8 (AAV8) vector (1.0×10E13 genome copies/mL) by the retroorbital route on Day-14. The recombinant AAV8 contained the open reading frame and the majority of the 3′UTR of the human MTRES1 sequence (NM_016487.5) under the control of the human thyroxine binding globulin promoter in an AAV2 backbone packaged in AAV8 capsid (AAV8-TBG-h-MTRES1). On Day 0, infected mice (n=8) were given a subcutaneous injection of a single 100 μg dose of a GalNAc-conjugated siRNA or PBS as vehicle control.

Mice were euthanized on Day 14 after subcutaneous injection and a liver sample from each was collected and placed in RNAlater (ThermoFisher Catalog #AM7020) until processing. Total liver RNA was prepared by homogenizing the liver tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer's recommendations. Preparation of cDNA was performed using Quanta qScript cDNA SuperMix (VWR, Catalog #95048-500) according to the manufacturer's instructions. The relative levels of liver MTRES1 mRNA were assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for human MTRES1 (ThermoFisher, assay #Hs01568158_g1) and the mouse housekeeping gene PPIA (ThermoFisher, assay #Mm02342430_g1) and PerfeCTa® qPCR FastMix®, Low ROX™ (VWR, Catalog #101419-222). Data were normalized to the mean MTRES1 mRNA level in animals receiving PBS. Results are shown in Table 51.

TABLE 49 Example siRNA Sequences Sense Anti- sense Strand Sense Strand Strand Antisense siRNA SEQ ID Sequence (5′-3′) SEQ ID Strand Sequence Name NO: with GalNAc moiety NO: (5′-3′) ETD02354 3091 [ETL17]suggcuAfGfuGfuuaaau 3179 usGfscAfaUfuUfaAfcAfcUfa ugcasusu GfcCfasusu ETD02355 3092 [ETL17]sggcuagUfgUfUfaaauu 3180 usAfsgCfaAfuUfuAfaCfaCfu gcuasusu AfgCfcsusu ETD02356 3093 [ETL17]sgcuagUfgUfUfaaauug 3181 usAfsaGfcAfaUfuUfaAfcAfc cuuasusu UfaGfcsusu ETD02357 3094 [ETL17]scggugUfUfUfUfaagaa 3182 usGfsgCfuUfuCfuUfaAfaAfc agccasusu AfcCfgsusu ETD02358 3095 [ETL17]sguacUfUfCfCfUfggaa 3183 usAfsuCfgAfuUfcCfaGfgAfa ucgauasusu GfuAfcsusu ETD02359 3096 [ETL17]scaaguuAfcGfuGfcacc 3184 usUfsuUfgGfuGfcAfcGfuAfa aaaasusu CfuUfgsusu ETD02360 3097 [ETL17]saaguUfaCfgUfgCfacc 3185 usAfsuUfuGfgUfgCfaCfgUfa aaauasusu AfcUfususu

TABLE 50 Example siRNA BASE Sequences Sense Strand Antisense Strand siRNA SEQ ID Base Sequence SEQ ID Base Sequence Name NO: (5′ to 3′) NO: (5′ to 3′) ETD02354 2786 UGGCUAGUGUUAAAUUGCAUU 2968 UGCAAUUUAACACUAGCCAUU ETD02355 2787 GGCUAGUGUUAAAUUGCUAUU 2969 UAGCAAUUUAACACUAGCCUU ETD02356 2788 GCUAGUGUUAAAUUGCUUAUU 2970 UAAGCAAUUUAACACUAGCUU ETD02357 2789 CGGUGUUUUAAGAAAGCCAUU 2971 UGGCUUUCUUAAAACACCGUU ETD02358 2790 GUACUUCCUGGAAUCGAUAUU 2972 UAUCGAUUCCAGGAAGUACUU ETD02359 2791 CAAGUUACGUGCACCAAAAUU 2973 UUUUGGUGCACGUAACUUGUU ETD02360 2792 AAGUUACGUGCACCAAAUAUU 2974 UAUUUGGUGCACGUAACUUUU Sense Strand Base Sense Strand Base Sequence (5′ to siRNA SEQ ID Sequence (5′ to 3′), SEQ ID 3′), without Name NO: without 3′ overhangs NO: 3′ overhangs ETD02354 2814 UGGCUAGUGUUAAAUUGCA 2996 UGCAAUUUAACACUAGCCA ETD02355 2815 GGCUAGUGUUAAAUUGCUA 2997 UAGCAAUUUAACACUAGCC ETD02356 2816 GCUAGUGUUAAAUUGCUUA 2998 UAAGCAAUUUAACACUAGC ETD02357 2817 CGGUGUUUUAAGAAAGCCA 2999 UGGCUUUCUUAAAACACCG ETD02358 2818 GUACUUCCUGGAAUCGAUA 3000 UAUCGAUUCCAGGAAGUAC ETD02359 2819 CAAGUUACGUGCACCAAAA 3001 UUUUGGUGCACGUAACUUG ETD02360 2820 AAGUUACGUGCACCAAAUA 3002 UAUUUGGUGCACGUAACUU

TABLE 51 Relative MTRES1 mRNA Levels in Livers of Mice Dose Mean MTRES1 mRNA (Normalized Group n Treatment (ug) to Group 1, Day 14) 2 8 PBS 1 3 8 ETD02354 100 0.48 4 8 ETD02355 100 0.57 5 8 ETD02356 100 0.36 6 8 ETD02357 100 0.57 7 8 ETD02358 100 0.35 8 8 ETD02359 100 0.54 9 8 ETD02360 100 0.37

Additional siRNAs targeting human MTRES1 mRNA and cross-reactive with at least cynomolgus monkey MTRES1 mRNA were tested for activity in mice following transfection with an adeno-associated viral vector. The siRNAs are conjugated to the GalNAc ligand ETL17. The siRNA sequences are shown in Tables 52A and 52B, where “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate linkage.

Six- to eight-week-old female mice (C57Bl/6) were injected with 5 μL of a recombinant adeno-associated virus 8 (AAV8) vector (1.0×10E13 genome copies/mL) by the retroorbital route on Day-14. The recombinant AAV8 contained the open reading frame and the majority of the 3′UTR of the human MTRES1 sequence (NM_016487.5) under the control of the human thyroxine binding globulin promoter in an AAV2 backbone packaged in AAV8 capsid (AAV8-TBG-h-MTRES1). On Day 0, infected mice (n=8) were given a subcutaneous injection of a single 100 μg dose of a GalNAc-conjugated siRNA or PBS as vehicle control.

Mice were euthanized on Day 14 after subcutaneous injection and a liver sample from each was collected and placed in RNAlater (ThermoFisher Catalog #AM7020) until processing. Total liver RNA was prepared by homogenizing the liver tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer's recommendations. Preparation of cDNA was performed using Quanta qScript cDNA SuperMix (VWR, Catalog #95048-500) according to the manufacturer's instructions. The relative levels of liver MTRES1 mRNA were assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for human MTRES1 (ThermoFisher, assay #Hs01568158_g1) and the mouse housekeeping gene PPIA (ThermoFisher, assay #Mm02342430_g1) and PerfeCTa® qPCR FastMix®, Low ROX™ (VWR, Catalog #101419-222). Data were normalized to the mean MTRES1 mRNA level in animals receiving PBS. Results are shown in Table 53.

TABLE 52A Example siRNA Sequences Sense Antisense Strand Strand siRNA SEQ ID Sense Strand Sequence  SEQ ID Antisense Strand  Name NO: (5′-3′) with GalNAc moiety NO: Sequence (5′-3′) ETD02361 3098 [ETL17]sguuaCfgUfgCfaCfcaa 3186 usUfsaAfuUfuGfgUfgCfaCfg auuaasusu UfaAfcsusu ETD02363 3100 [ETL17]sgucuAfcAfAfAfAfuc 3188 usUfsuAfgUfaGfaUfuUfuGfu uacuaaasusu AfgAfcsusu ETD02364 3101 [ETL17]sagucUfUfUfUfCfggu 3189 usCfsaUfcAfuAfcCfgAfaAfa augaugasusu GfaCfususu ETD02365 3102 [ETL17]sggcuAfgAfuAfuuggg 3190 usUfsuCfuCfcCfaAfuAfuCfu agaaasusu AfgCfcsusu ETD02366 3103 [ETL17]sagauAfuuGfGfGfAfg 3191 usUfsuGfuUfuCfuCfcCfaAfu aaacaaasusu AfuCfususu ETD02367 3104 [ETL17]sgauacAfuuGfGfaucuu 3192 usGfsaGfaAfgAfuCfcAfaUfg cucasusu UfaUfcsusu

TABLE 52B Example siRNA BASE Sequences siRNA SEQ ID Sense Strand Base Sequence SEQ ID Antisense Strand Base Sequence Name NO: (5′ to 3′) NO: (5′ to 3′) ETD02361 2793 GUUACGUGCACCAAAUUAAUU 2975 UUAAUUUGGUGCACGUAACUU ETD02363 2795 GUCUACAAAAUCUACUAAAUU 2977 UUUAGUAGAUUUUGUAGACUU ETD02364 2796 AGUCUUUUCGGUAUGAUGAUU 2978 UCAUCAUACCGAAAAGACUUU ETD02365 2797 GGCUAGAUAUUGGGAGAAAUU 2979 UUUCUCCCAAUAUCUAGCCUU ETD02366 2798 AGAUAUUGGGAGAAACAAAUU 2980 UUUGUUUCUCCCAAUAUCUUU ETD02367 2799 GAUACAUUGGAUCUUCUCAUU 2981 UGAGAAGAUCCAAUGUAUCUU siRNA SEQ ID Sense Strand Base Sequence (5′ SEQ ID Sense Strand Base Sequence (5′ Name NO: to 3′), without 3′ overhangs NO: to 3′), without 3′ overhangs ETD02361 2821 GUUACGUGCACCAAAUUAA 3003 UUAAUUUGGUGCACGUAAC ETD02363 2823 GUCUACAAAAUCUACUAAA 3005 UUUAGUAGAUUUUGUAGAC ETD02364 2824 AGUCUUUUCGGUAUGAUGA 3006 UCAUCAUACCGAAAAGACU ETD02365 2825 GGCUAGAUAUUGGGAGAAA 3007 UUUCUCCCAAUAUCUAGCC ETD02366 2826 AGAUAUUGGGAGAAACAAA 3008 UUUGUUUCUCCCAAUAUCU ETD02367 2827 GAUACAUUGGAUCUUCUCA 3009 UGAGAAGAUCCAAUGUAUC

TABLE 53 Relative MTRES1 mRNA Levels in Livers of Mice Dose Mean MTRES1 mRNA (Normalized Group n Treatment (ug) to Group 1, Day 14) 2 8 PBS 1 3 8 ETD02361 100 1.37 5 8 ETD02363 100 1.2 6 8 ETD02364 100 1.41 7 8 ETD02365 100 0.39 8 8 ETD02366 100 0.82 9 8 ETD02367 100 0.95

Additional siRNAs targeting human MTRES1 mRNA and cross-reactive with at least cynomolgus monkey MTRES1 mRNA were tested for activity in mice following transfection with an adeno-associated viral vector. The siRNAs are conjugated to the GalNAc ligand ETL17. The siRNA sequences are shown in Tables 54A and 54B, where “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate linkage.

Six- to eight-week-old female mice (C57Bl/6) were injected with 5 μL of a recombinant adeno-associated virus 8 (AAV8) vector (1.6×10E13 genome copies/mL) by the retroorbital route on Day-14. The recombinant AAV8 contained the open reading frame and the majority of the 3′UTR of the human MTRES1 sequence (NM_016487.5) under the control of the human thyroxine binding globulin promoter in an AAV2 backbone packaged in AAV8 capsid (AAV8-TBG-h-MTRES1). On Day 0, infected mice (n=8) were given a subcutaneous injection of a single 100 μg dose of a GalNAc-conjugated siRNA or PBS as vehicle control.

Mice were euthanized on Day 14 after subcutaneous injection and a liver sample from each was collected and placed in RNAlater (ThermoFisher Catalog #AM7020) until processing. Total liver RNA was prepared by homogenizing the liver tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer's recommendations. Preparation of cDNA was performed using Quanta qScript cDNA SuperMix (VWR, Catalog #95048-500) according to the manufacturer's instructions. The relative levels of liver MTRES1 mRNA were assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for human MTRES1 (ThermoFisher, assay #Hs01568158_g1) and the mouse housekeeping gene PPIA (ThermoFisher, assay #Mm02342430_g1) and PerfeCTa® qPCR FastMix®, Low ROX™ (VWR, Catalog #101419-222). Data were normalized to the mean MTRES1 mRNA level in animals receiving PBS. Results are shown in Table 55.

TABLE 54A Example siRNA Sequences Sense Antisense Strand Strand siRNA SEQ ID Sense Strand Sequence (5′-3′) SEQ ID Antisense Strand  Name NO: with GalNAc moiety NO: Sequence (5′-3′) ETD02368 3105 [ETL17]sucuuCfuCfaUfUfggag 3193 usUfscCfuCfuCfcAfaUfgAfg aggaasusu AfaGfasusu ETD02369 3106 [ETL17]scucauuGfGfAfGfAfg 3194 usUfsuUfaUfcCfuCfuCfcAfa gauaaaasusu UfgAfgsusu ETD02370 3107 [ETL17]sggauAfaAfGfAfAfgc 3195 usGfsuUfcCfuGfcUfuCfuUfu aggaacasusu AfuCfcsusu ETD02371 3108 [ETL17]sagagaCfagUfUfaugcg 3196 usAfsuCfcGfcAfuAfaCfuGfu gauasusu CfuCfususu ETD02372 3109 [ETL17]sagacAfGfuuAfuGfcg 3197 usGfsaAfuCfcGfcAfuAfaCfu gauucasusu GfuCfususu ETD02373 3110 [ETL17]scaguUfaUfgCfggauuc 3198 usAfsgAfgAfaUfcCfgCfaUfa ucuasusu AfcUfgsusu ETD02374 3111 [ETL17]suuauGfcGfgAfuucucu 3199 usUfscAfaGfaGfaAfuCfcGfc ugaasusu AfuAfasusu

TABLE 54B Example siRNA BASE Sequences siRNA SEQ ID Sense Strand Base Sequence SEQ ID Antisense Strand Base Sequence Name NO: (5′ to 3′) NO: (5′ to 3′) ETD02368 2800 UCUUCUCAUUGGAGAGGAAUU 2982 UUCCUCUCCAAUGAGAAGAUU ETD02369 2801 CUCAUUGGAGAGGAUAAAAUU 2983 UUUUAUCCUCUCCAAUGAGUU ETD02370 2802 GGAUAAAGAAGCAGGAACAUU 2984 UGUUCCUGCUUCUUUAUCCUU ETD02371 2803 AGAGACAGUUAUGCGGAUAUU 2985 UAUCCGCAUAACUGUCUCUUU ETD02372 2804 AGACAGUUAUGCGGAUUCAUU 2986 UGAAUCCGCAUAACUGUCUUU ETD02373 2805 CAGUUAUGCGGAUUCUCUAUU 2987 UAGAGAAUCCGCAUAACUGUU ETD02374 2806 UUAUGCGGAUUCUCUUGAAUU 2988 UUCAAGAGAAUCCGCAUAAUU siRNA SEQ ID Sense Strand Base Sequence (5′ SEQ ID Sense Strand Base Sequence (5′ Name NO: to 3′), without 3′ overhangs NO: to 3′), without 3′ overhangs ETD02368 2828 UCUUCUCAUUGGAGAGGAA 3010 UUCCUCUCCAAUGAGAAGA ETD02369 2829 CUCAUUGGAGAGGAUAAAA 3011 UUUUAUCCUCUCCAAUGAG ETD02370 2830 GGAUAAAGAAGCAGGAACA 3012 UGUUCCUGCUUCUUUAUCC ETD02371 2831 AGAGACAGUUAUGCGGAUA 3013 UAUCCGCAUAACUGUCUCU ETD02372 2832 AGACAGUUAUGCGGAUUCA 3014 UGAAUCCGCAUAACUGUCU ETD02373 2833 CAGUUAUGCGGAUUCUCUA 3015 UAGAGAAUCCGCAUAACUG ETD02374 2834 UUAUGCGGAUUCUCUUGAA 3016 UUCAAGAGAAUCCGCAUAA

TABLE 55 Relative MTRES1 mRNA Levels in Livers of Mice Dose Mean MTRES1 mRNA (Normalized Group n Treatment (ug) to PBS Group, Day 14) 2 8 PBS 1 3 8 ETD02368 100 1.84 4 8 ETD02369 100 0.79 5 8 ETD02370 100 0.97 6 8 ETD02371 100 2.03 7 8 ETD02372 100 1.09 8 8 ETD02373 100 0.51 9 8 ETD02374 100 0.8

ETD02077, ETD02182 and ETD02177 and siRNAs of the same base sequences containing alternative modifications were tested for activity in mice following transfection with an adeno-associated viral vector expressing human MTRES1. The siRNAs are conjugated to the GalNAc ligand ETL17. The siRNA sequences are shown in Tables 56 and 57, where “Nf” is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate linkage.

Six- to eight-week-old female mice (C57Bl/6) were injected with 5 μL of a recombinant adeno-associated virus 8 (AAV8) vector (1.6×10E13 genome copies/mL) by the retroorbital route on Day-14. The recombinant AAV8 contained the open reading frame and the majority of the 3′UTR of the human MTRES1 sequence (NM_016487.5) under the control of the human thyroxine binding globulin promoter in an AAV2 backbone packaged in AAV8 capsid (AAV8-TBG-h-MTRES1). On Day 0, infected mice (n=8) were given a subcutaneous injection of a single 60 μg or 100 μg dose of a GalNAc-conjugated siRNA or PBS as vehicle control.

Mice were euthanized on Day 11 after subcutaneous injection and a liver sample from each was collected and placed in RNAlater (ThermoFisher Catalog #AM7020) until processing. Total liver RNA was prepared by homogenizing the liver tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer's recommendations. Preparation of cDNA was performed using Quanta qScript cDNA SuperMix (VWR, Catalog #95048-500) according to the manufacturer's instructions. The relative levels of liver MTRES1 mRNA were assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for human MTRES1 (ThermoFisher, assay #Hs01568158_g1) and the mouse housekeeping gene PPIA (ThermoFisher, assay #Mm02342430_g1) and PerfeCTa® qPCR FastMix®, Low ROX™ (VWR, Catalog #101419-222). Data were normalized to the mean MTRES1 mRNA level in animals receiving PBS. Results are shown in Table 58.

TABLE 56 Example siRNA Sequences Sense Antisense Strand Strand siRNA SEQ ID Sense Strand Sequence  SEQ ID Antisense Strand Sequence Name NO: (5′-3′) with GalNAc moiety NO: (5′-3′) ETD02077 3084 [ETL17]sgaagAfAfAfAfGfcag 3171 usAfscCfgUfuCfuGfcUfuUfu aacgguasusu CfuUfcsusu ETD02192 3259 [ETL17]sgaagAfAfAfAfGfcag 3261 usAfsccGfuUfcuGfcUfuUfuCf aacgguasusu uUfcsusu ETD02182 3088 [ETL17]sucuacAfAfAfGfGfug 3176 usUfsgagUfuCfaCfcUfuUfgUf aacucaasusu aGfasusu ETD02185 3090 [ETL17]sucuacAfAfAfGfGfug 3178 usUfsgAfguUfcAfccuuUfgUfa aacucaasusu Gfasusu ETD02177 3074 [ETL17]saagaAfaAfGfCfagaac 3161 usCfsaCfcGfuUfcUfgCfuUfu ggugasusu UfcUfususu ETD02406 3260 [ETL17]saagaaAfAfGfCfagaac 3262 usCfsaCfcGfuUfcUfgCfuUfu ggugasusu UfcUfususu

TABLE 57 Example siRNA BASE Sequences SEQ SEQ siRNA ID Sense Strand Base  ID Antisense Strand Base  Name NO: Sequence (5′ to 3′) NO: Sequence (5′ to 3′) ETD02077 2771 GAAGAAAAGCAGAACGGUAUU 2953 UACCGUUCUGCUUUUCUUCUU ETD02192 2773 GAAGAAAAGCAGAACGGUAUU 2955 UACCGUUCUGCUUUUCUUCUU ETD02182 2775 UCUACAAAGGUGAACUCAAUU 2957 UUGAGUUCACCUUUGUAGAUU ETD02185 2777 UCUACAAAGGUGAACUCAAUU 2959 UUGAGUUCACCUUUGUAGAUU ETD02177 2744 AAGAAAAGCAGAACGGUGAUU 2926 UCACCGUUCUGCUUUUCUUUU ETD02406 3263 AAGAAAAGCAGAACGGUGAUU 3265 UCACCGUUCUGCUUUUCUUUU SEQ Sense Strand Base  SEQ Sense Strand Base  siRNA ID Sequence (5′ to 3′), ID Sequence (5′ to 3′), Name NO: without 3′ overhangs NO: without 3′ overhangs ETD02077 2779 GAAGAAAAGCAGAACGGUA 2961 UACCGUUCUGCUUUUCUUC ETD02192 2781 GAAGAAAAGCAGAACGGUA 2963 UACCGUUCUGCUUUUCUUC ETD02182 2783 UCUACAAAGGUGAACUCAA 2965 UUGAGUUCACCUUUGUAGA ETD02185 2785 UCUACAAAGGUGAACUCAA 2967 UUGAGUUCACCUUUGUAGA ETD02177 2753 AAGAAAAGCAGAACGGUGA 2935 UCACCGUUCUGCUUUUCUU ETD02406 3264 AAGAAAAGCAGAACGGUGA 3266 UCACCGUUCUGCUUUUCUU

TABLE 58 Relative MTRES1 mRNA Levels in Livers of Mice Dose Mean MTRES1 mRNA (Normalized Group n Treatment (ug) to PBS Group, Day 11) 2 8 PBS 1 3 8 ETD02077 60 1.63 4 8 ETD02192 60 0.84 5 8 ETD02182 60 0.72 6 8 ETD02185 60 0.61 7 8 ETD02177 100 0.32 8 8 ETD02406 100 0.55

The base sequence of ETD02177 was synthesized with alternative modification patterns and then tested for activity in mice. The siRNA sequences are shown in Table 59 and 60, where Nf is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, “nm” is a 2′-O-methoxyethyl modified nucleoside, and “s” is a phosphorothioate linkage. All siRNAs were conjugated to the GalNAc ligand ETL17.

Six- to eight-week-old female mice (strain ICR, n=3) were given a subcutaneous injection on Day 0 of a single 100 μg dose of a GalNAc-conjugated siRNA or PBS as vehicle control.

Mice were euthanized on Day 14 after injection and a liver sample from each was collected and placed in RNAlater (ThermoFisher Catalog #AM7020) until processing. Total liver RNA was prepared by homogenizing the liver tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer's recommendations. Preparation of cDNA was performed using Quanta qScript cDNA SuperMix (VWR, Catalog #95048-500) according to the manufacturer's instructions. The relative levels of liver MTRES1 mRNA were assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for mouse MTRES1 (ThermoFisher, assay #Mm01229834_m1) and the mouse housekeeping gene PPIA (ThermoFisher, assay #Mm02342430_g1) and PerfeCTaR qPCR FastMix®, Low ROX™ (VWR, Catalog #101419-222). Data were normalized to the mean MTRES1 mRNA level in animals receiving PBS. Results are shown in Table 61. ETD02177 and all of the alternatively modified versions of ETD02177 gave a reduction in mouse MTRES1 liver mRNA after administration. Mice receiving ETD02409 had the highest level of mean MTRES1 mRNA knockdown in the liver.

TABLE 59 Example siRNA Sequences Sense Antisense Strand Strand siRNA SEQ ID Sense Strand Sequence SEQ ID Antisense Strand Sequence Name NO: (5′-3′) with GalNAc moiety NO: (5′-3′) ETD02177 3074 [ETL17]saagaAfaAfGfCfagaac 3161 usCfsaCfcGfuUfcUfgCfuUfu ggugasusu UfcUfususu ETD02406 3267 [ETL17]saagaaAfAfGfCfagaac 3274 usCfsaCfcGfuUfcUfgCfuUfu ggugasusu UfcUfususu ETD02407 3268 [ETL17]saagamaAfAfGfCfaga 3275 usCfsaCfcGfuUfcUfgCfuUfu acgmgugasusu UfcUfususu ETD02408 3269 [ETL17]saagamaAfAfGfCfaga 3276 usCfsaCfcGfuUfcUfgCfuUfu acmggugasusu UfcUfususu ETD02409 3270 [ETL17]saagamaAfAfGfCfaga 3277 usCfsaCfcGfuUfcUfgCfuUfu amcggugasusu UfcUfususu ETD02410 3271 [ETL17]saagamaAfAfGfCfaga 3278 usCfsaCfcGfuUfcUfgCfuUfu macggugasusu UfcUfususu ETD02411 3272 [ETL17]saagaamAfAfGfCfaga 3279 usCfsaCfcGfuUfcUfgCfuUfu macggugasusu UfcUfususu ETD02412 3273 [ETL17]saagaamAfAfGfCfaga 3280 usCfsaCfcGfuUfcUfgCfuUfu amcggugasusu UfcUfususu

TABLE 60 Example siRNA BASE Sequences SEQ Sense Strand Base  SEQ Antisense Strand Base siRNA ID Sequence (5′ to 3′), ID Sequence (5′ to 3′), Name NO: without 3′ overhangs NO: without 3′ overhangs ETD02177 3074 AAGAAAAGCAGAACGGUGA 3161 UCACCGUUCUGCUUUUCUU ETD02406 3281 AAGAAAAGCAGAACGGUGA 3288 UCACCGUUCUGCUUUUCUU ETD02407 3282 AAGAAAAGCAGAACGGUGA 3289 UCACCGUUCUGCUUUUCUU ETD02408 3283 AAGAAAAGCAGAACGGUGA 3290 UCACCGUUCUGCUUUUCUU ETD02409 3284 AAGAAAAGCAGAACGGUGA 3291 UCACCGUUCUGCUUUUCUU ETD02410 3285 AAGAAAAGCAGAACGGUGA 3293 UCACCGUUCUGCUUUUCUU ETD02411 3286 AAGAAAAGCAGAACGGUGA 3294 UCACCGUUCUGCUUUUCUU ETD02412 3287 AAGAAAAGCAGAACGGUGA 3295 UCACCGUUCUGCUUUUCUU

TABLE 61 Relative MTRES1 mRNA Levels in Livers of Mice Dose Mean MTRES1 mRNA (Normalized Group n Treatment (ug) to Group 1, Day 14) 1 3 PBS 1 2 3 ETD02177 100 0.52 3 3 ETD02406 100 0.35 4 3 ETD02407 100 0.27 5 3 ETD02408 100 0.3 6 3 ETD02409 100 0.11 7 3 ETD02410 100 0.29 8 3 ETD02411 100 0.22 9 3 ETD02412 100 0.3

The siRNA sequences are shown in Tables 62A-62B, where Nf is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, “nm” is a 2′-O-methoxyethyl modified nucleoside, and “s” is a phosphorothioate linkage. 5VP is vinyl phosphonate at 5′ end of antisense strand using 5′-POM-vinyl phosphonate, 2′-OMe-U CE-Phosphoramidite (Biosearch Technologies, 2579).

−1 Mice were induced to anesthetic states in an induction chamber with 1.2% isoflurane vaporized by oxygen of 1.0 L/min and then transferred and fixed to a stereotaxic frame while keeping anesthetized by 0.8% isoflurane through a mask. Skull was exposed and single intracerebroventricular injections (5 μL, artificial cerebrospinal fluid as vehicle) were performed at 500 nL minafter needle placement at the following coordinates from bregma: −0.2 mm anterior-posterior, 0.8 mm mediolateral and −2.5 mm dorsoventral using a Standard U-Frame Stereotaxic Instrument for Mouse (Harvard Apparatus 75-1808) and a Stereotaxic Anesthesia Adapters with Anesthesia Masks (Harvard Apparatus 75-1856).

TABLE 62A siRNA duplexes SEQ SEQ  ID ID Antisense Entity # NO Sense Strand NO Strand ETD02550 3296 [ETL20]aagam 3300 5VPusCfsaC aAfAfGfCfaga fcGfuUfcUf amcggugasusu gCfuUfuUfc Ufususu

TABLE 62B siRNA duplexes base sequences SEQ SEQ ID ID Antisense Entity # NO Sense Strand NO Strand ETD02550 2698 AAGAAAAGCAGA 2880 UCACCGUUCU ACGGUGA GCUUUUCUU

Mice were euthanized on day 14 post-injection. Brains from each animal were harvested and dissected into right and left hemispheres.

Total RNA was extracted from homogenized tissue and reverse transcribed to cDNA using a First-Strand III cDNA Synthesis kit. Normalized cDNA quantification was carried out by real-time TaqMan PCR using fluorescently labeled TaqMan assays for mouse MTRES1 (ThermoFisher, assay #Mm01229834_m1) and the mouse housekeeping gene PPIA (ThermoFisher, assay #Mm02342430_g1). Reactions were carried out in 20 μL aliquots using TaqMan Universal PCR Master Mix No AmpErase UNG ran on an ABI Prism 7500 Fast Real-Time PCR System Sequence Detection System and analyzed by the 7500 System software. Relative Quantification (RQ) values between treated and untreated samples are calculated by the formula 2-ΔΔCT, where CT is the cycle at threshold (automatic measurement), ΔCT is CT of the assayed gene (MTRES1) minus CT of the endogenous control (PPIA), and ΔΔCT is the ΔCT of the normalized assayed gene in the treated sample minus the ΔCT of the same gene in the untreated one (calibrator). Results are depicted in Table 63.

TABLE 63 Relative MTRES1 mRNA Levels in Brains of Mice siRNA Average mRNA relative to no treatment control animals 50 μg dose ETD02550 0.18

The siRNA sequences are shown in Tables 64A-64B, where Nf is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, “nm” is a 2′-O-methoxyethyl modified nucleoside, and “s” is a phosphorothioate linkage. 5VP is vinyl phosphonate at 5′ end of antisense strand using 5′-POM-vinyl phosphonate, 2′-OMe-U CE-Phosphoramidite (Biosearch Technologies, 2579).

−1 Mice were induced to anesthetic states in an induction chamber with 1.2% isoflurane vaporized by oxygen of 1.0 L/min and then transferred and fixed to a stereotaxic frame while keeping anesthetized by 0.8% isoflurane through a mask. Skull was exposed and single intracerebroventricular injections (5 μl, artificial cerebrospinal fluid as vehicle) were performed at 500 nl minafter needle placement at the following coordinates from bregma: −0.2 mm anterior-posterior, 0.8 mm mediolateral and −2.5 mm dorsoventral using a Standard U-Frame Stereotaxic Instrument for Mouse (Harvard Apparatus 75-1808) and a Stereotaxic Anesthesia Adapters with Anesthesia Masks (Harvard Apparatus 75-1856). 6 mice were tested in each group.

TABLE 64A siRNA duplexes SEQ SEQ posi- ID Sense  ID Antisense Entity # tion NO Strand NO Strand ETD02209 574 3297 [ELT20]cuA 3301 usCfsugaG fcAfaAfgGf fuUfcaccu uGfaAfcucA UfuGfuags fgAfsusu usu ETD02137 574 3298 [ELT20]cuA 3302 5VPusCfsu fcAfaAfgGf gaGfuUfca uGfaAfcucA ccuUfuGfu fgAfsusu agsusu

TABLE 64B siRNA duplexes base sequences SEQ SEQ ID ID Entity # NO Sense Strand NO Antisense Strand ETD02209 2555 CUACAAAGGUGA 2617 UCUGAGUUCACCUUUG ACUCAGA UAG ETD02137 2555 CUACAAAGGUGA 2617 UCUGAGUUCACCUUUG ACUCAGA UAG

Mice were euthanized on 14, 28 days, 3 or 6 months post-injection. Brains from each animal were harvested and dissected into right and left hemispheres.

Total RNA was extracted from homogenized tissue and reverse transcribed to cDNA using a First-Strand III cDNA Synthesis kit. Normalized cDNA quantification was carried out by real-time TaqMan PCR using fluorescently labeled TaqMan assays for mouse MTRES1 (ThermoFisher, assay #Mm01229834_m1) and the mouse housekeeping gene PPIA (ThermoFisher, assay #Mm02342430_g1). Reactions were carried out in 20 μL aliquots using TaqMan Universal PCR Master Mix No AmpErase UNG ran on an ABI Prism 7500 Fast Real-Time PCR System Sequence Detection System and analyzed by the 7500 System software. Relative Quantification (RQ) values between treated and untreated samples are calculated by the formula 2-ΔΔCT, where CT is the cycle at threshold (automatic measurement), ΔCT is CT of the assayed gene (MTRES1) minus CT of the endogenous control (PPIA), and ΔΔCT is the ΔCT of the normalized assayed gene in the treated sample minus the ΔCT of the same gene in the untreated one (calibrator). Results are depicted in Table 65.

TABLE 65 Relative MTRES1 mRNA Levels in Brains of Mice No Treatment SD 100 ug 2209 SD 100 ug 2137 SD 14 days 1 0.1 0.22 0.32 0.02 0 28 days 1 0.11 0.02 0.01 0.02 0.01  3 Month 1 0.04 0.38 0.37 0.05 0.04  6 Month 1 0.04 0.79 0.13 0.12 0.09

−1 Duplexes formulated at 30 mg mlin 0.9% NaCl in water were administered as 30-μl IT injections by lumbar puncture in the dorsal region of the spine between the L5 and L6 vertebral space to male Sprague Dawley rats (N=5 or 6) 250-300 g. After anesthesia with isoflurane, rats were placed on a warm heating pad; the IT injection site was shaved and disinfected. The rats were put in a prone position, and held at the height of the iliac crest, hind legs pointing out- and downward. The injection site was identified by palpation and marked on the skin. After identification of the puncture site, an insulin syringe was inserted between the L5 and L6 spinous processes. Once in contact with the spinal column bone, the syringe angle was reduced to approximately 30° and carefully pushed forward into the intervertebral space. Piercing of the dura mater caused a reflexive tail or limb flick, which is used as an indication of the needle being in the correct location. Once the indication of dura puncture was observed, the test article was delivered as a bolus dose (within ~2 s) in a volume of 30 μL. The needle was then be kept in place for an additional 5 s before withdrawal of the needle with a slow rotating movement. The animals were then allowed to recover.

Rats were euthanized on Day 14 after injection and samples of liver, kidney, R/L frontal cortex, R/L temporal cortex, hippocampus, brain stem, cerebellum and the spinal cord from each were collected and placed in RNAlater (ThermoFisher Catalog #AM7020) until processing. Total liver RNA was prepared by homogenizing the liver tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer's recommendations. Preparation of cDNA was performed using Quanta qScript cDNA SuperMix (VWR, Catalog #95048-500) according to the manufacturer's instructions. The relative levels of MTRES1 mRNA were assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for rat MTRES1 (ThermoFisher, assay #Rn01441122_m1) and the rat housekeeping gene PPIA (ThermoFisher, assay #Rn03302269_gH) and PerfeCTaR qPCR FastMix®, Low ROX™ (VWR, Catalog #101419-222). Data were normalized to the mean MTRES1 mRNA level in animals receiving vehicle (saline) control. Results are shown in Table 66. The siRNA sequences are shown in Tables 67A-67B, where Nf is a 2′-fluoro-modified nucleoside, “n” is a 2′-O-methyl modified nucleoside, “nm” is a 2′-O-methoxyethyl modified nucleoside, and “s” is a phosphorothioate linkage

TABLE 66 Relative MTRES1 mRNA Levels in Brains of Mice. vehicle control ETD02210 ETD02211 ETD02275 relative relative relative relative tissue mRNA SD n mRNA SD n mRNA SD n mRNA SD n Spinal Cord 1.02 0.21 6 0.02 0.02 6 0.15 0.22 6 0.11 0.04 6 Cerebellum 1 0.06 6 0.03 0.03 6 0.22 0.19 6 0.18 0.04 6 Hippocampus 1.01 0.18 5 0.03 0.02 6 0.28 0.27 5 0.24 0.11 6 Brain Stem 1.05 0.29 6 0.02 0.01 6 0.23 0.19 6 0.23 0.05 6 Frontal 1.01 0.16 5 0.04 0.02 6 0.33 0.21 6 0.25 0.09 6 Cortex Left Frontal 1.03 0.25 6 0.03 0.02 6 0.34 0.3 6 0.24 0.09 6 Cortex Right Temporal 1.01 0.14 6 0.03 0.01 6 0.28 0.32 6 0.22 0.04 6 Cortex Left Temporal 1.02 0.19 6 0.02 0.01 6 0.36 0.35 6 0.2 0.07 6 Cortex Right vehicle control ETD02274 ETD02804 ETD02789 relative relative relative relative tissue mRNA SD n mRNA SD n mRNA SD n mRNA SD n Kidney 1.04 0.32 6 0.25 0.08 6 0.6 0.11 6 0.86 0.21 6 Liver 1.03 0.25 6 0.27 0.05 6 0.61 0.16 6 0.77 0.12 6 Lumbar 1.02 0.22 6 0.19 0.35 6 0.32 0.36 6 1.14 0.21 6 Spinal Cord Thoracic 1.02 0.23 6 0.31 0.45 6 0.37 0.37 6 1.04 0.07 6 Spinal Cord Cervical 1.02 0.2 6 0.32 0.36 6 0.53 0.41 6 1.04 0.12 6 Spinal Cord Cerebellum 1.03 0.24 6 0.31 0.55 6 0.8 0.28 6 1.13 0.11 6 Brain Stem 1.06 0.34 6 0.3 0.25 6 0.62 0.3 6 1.01 0.25 6 Hippocampus 1 0.07 6 0.55 0.49 6 0.75 0.3 6 0.95 0.06 6 Liver 1.03 0.25 6 0.27 0.05 6 0.61 0.16 6 0.77 0.12 6 Temporal 1.03 0.31 6 0.6 0.47 6 0.79 0.19 6 0.93 0.22 6 Cortex Left Temporal 1.07 0.43 6 0.49 0.46 6 0.66 0.17 6 1.06 0.35 6 Cortex Right Frontal 1.04 0.26 6 0.49 0.55 6 1.04 0.5 6 0.86 0.14 6 Cortex Left Frontal 1.2 0.82 6 0.46 0.56 6 0.73 0.16 6 0.87 0.23 6 Cortex Right

TABLE 67A siRNA sequences SEQ SEQ ID Duplexes ID Duplexes Entity # NO Sense Strand AXO Format NO Antisense Strand AXO Format ETD02210 3241 [ETL20]ucuacAfAfAfGfGfugaacucaasusu 3244 5VPusUfsgAfgUfuCfaCfcUfuUfgUfaGfasusu ETD02211 3242 [ETL20]gaagAfAfAfAfGfcagaacgguasusu 3245 5VPusAfscCfgUfuCfuGfcUfuUfuCfuUfcsusu ETD02274 3241 [ETL20]ucuacAfAfAfGfGfugaacucaasusu 3247 5VPusUfsgaGfuUfcaCfcUfuUfgUfaGfasusu ETD02275 3242 [ETL20]gaagAfAfAfAfGfcagaacgguasusu 3248 5VPusAfsccgUfuCfuGfcUfuUfuCfuUfcsusu ETD02804 3299 [ETL20]suscuacAfAfAfGfGfugaacucaasusu 3304 5VPusUfsgaGfuUfcaCfcUfuUfgUfaGfasusu

TABLE 67B siRNA base sequences Duplexes SEQ Duplexes SEQ Antisense ID Sense Strand ID Strand Entity # NO AXO Format NO AXO Format ETD02210 2721 UCUACAAAGGUG 2903 UUGAGUUCAC AACUCAA CUUUGUAGA ETD02211 2729 GAAGAAAAGCAG 2911 UACCGUUCUG AACGGUA CUUUUCUUC ETD02274 2721 UCUACAAAGGUG 2903 UUGAGUUCAC AACUCAA CUUUGUAGA ETD02275 2729 GAAGAAAAGCAG 2911 UACCGUUCUG AACGGUA CUUUUCUUC ETD02804 2720 UCUACAAAGGUG 2902 UUGAGUUCAC AACUCAA CUUUGUAGA

All positions of the sense strand are 2′F, 2′-O-methoxyethyl, or 2′-O-methyl All antisense strands are 2′F or 2′-O-methyl An example siRNA includes a combination of the following modifications:

Positions 6-9 of the sense strand is 2′F. Positions 4 or 5 of the sense strand is 2′-O-methoxyethyl Positions 16-20 of the sense strand are 2′-O-methyl. All remaining positions of the sense strand are 2′F, 2′-O-methoxyethyl, or 2′-O-methyl All antisense strands are 2′F or 2′-O-methyl An example siRNA includes a combination of the following modifications:

The base sequences of ETD02406 were synthesized with alternative modification patterns and then tested for activity in mice. The siRNAs were attached to the GalNAc ligand ETL17. The siRNA sequences are shown in Table 68, where Nf is a 2′-fluoro-modified nucleoside, n is a 2′-O-methyl modified nucleoside, nm is a 2′-O-(2-methoxyethyl) modified nucleoside, and “s” is a phosphorothioate linkage. Base sequences are shown in Table 69.

Six- to eight-week-old female mice (strain ICR, n=3) were given a subcutaneous injection on Day 0 of a single 50 μg dose of a GalNAc-conjugated siRNA or PBS as vehicle control.

Mice were euthanized on Day 14 after injection and a liver sample from each was collected and placed in RNAlater (ThermoFisher Catalog #AM7020) until processing. Total liver RNA was prepared by homogenizing the liver tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer's recommendations. Preparation of cDNA was performed using Quanta qScript cDNA SuperMix (VWR, Catalog #95048-500) according to the manufacturer's instructions. The relative levels of liver MTRES1 mRNA were assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for mouse MTRES1 (ThermoFisher, assay #Mm00471319_m1) and the mouse housekeeping gene PPIA (ThermoFisher, assay #Mm02342430_g1) and PerfeCTa® qPCR FastMix®, Low ROX™ (VWR, Catalog #101419-222). Data were normalized to the mean MTRES1 mRNA level in animals receiving PBS. Results are shown in Table 70. Of the alternatively modified versions of ETD02406, mice injected with ETD02417, ETD02409, ETD02420, or ETD02418 had greatest reductions in mean liver MTRES1 mRNA on Day 14 relative to mice receiving PBS.

TABLE 68 Example siRNA Sequences Sense Anti- Strand sense SEQ Sense Strand  Strand siRNA ID Sequence (5′-3′)  SEQ ID Antisense Strand Sequence Name NO: with GalNAc moiety NO: (5′-3′) ETD02406 3305 [ETL17]saagaaAfAfG 3135 usCfsaCfcGfuUfcUfgCfuUfuUf fCfagaacggugasusu cUfususu ETD02409 3306 [ETL17]saagamaAfAf 3135 usCfsaCfcGfUfcUfgCfuUfuUf GfCfagaamcggugasusu cUfususu ETD02413 3305 [ETL17]saagaaAfAfGf 3319 usCfsaccGfuUfcUfgCfuUfuUfc Cfagaacggugasusu Ufususu ETD02414 3305 [ETL17]saagaaAfAfGf 3320 usCfsaccGfuUfcUfgcuUfuUfeUf Cfagaacggugasusu USUSU ETD02415 3305 [ETL17]saagaaAfAfGf 3321 usCfsaccGfuUfcugCfuUfuUfcUf Cfagaacggugasusu usuSU ETD02416 3305 [ETL17]saagaaAfAfG 3322 usCfsaCfogUfucUfgCfuUfuUfc fCfagaacggugasusu Ufususu ETD02417 3305 [ETL17]saagaaAfAfG 3323 usCfsacCfgUfucUfgCfuUfuUfc fCfagaacggugasUSU Ufususu ETD02418 3305 [ETL17]saagaaAfAfG 3324 usCfsacCfgUfuCfugcuUfuUfeUf fCfagaaeggugasuSU USUSU ETD02419 3305 [ETL17]saagaaAfAfG 3325 usCfsacCfgUfucUfgcuUfuUfcUf fCfagaacggugasuso ususu ETD02420 3305 [ETL17]saagaaAfAfG 3326 usCfsacCfgUfucUfgcuUfUfcuu fCfagaacggugasUSU suSu ETD02182 3051 [ETL17]socuacAfAfA 3142 usUfsgagUfuCfaCfcUfuUfgUfa fGfGfugaacucaasusu Gfasusu ETD02459 3051 [ETL17]sucuacAfAfA 3327 usUfsgagUfuCfaCfcUfuUfgUfa fGfGfugaacucaasusu gasusu

TABLE 69 Example siRNA BASE Sequences Sense Antisense Strand Strand SEQ Base SEQ Base siRNA ID Sequence ID Sequence Name NO: (5′ to 3′) NO: (5′ to 3′) ETD02406 2684 AAGAAAAGCA 2866 UCACCGUUCU GAACGGUGAU GCUUUUCUUU U U ETD02409 2684 AAGAAAAGCA 2866 UCACCGUUCU GAACGGUGAU GCUUUUCUUU U U ETD02413 2684 AAGAAAAGCA 2866 UCACCGUUCU GAACGGUGAU GCUUUUCUUU U U ETD02414 2684 AAGAAAAGCA 2866 UCACCGUUCU GAACGGUGAU GCUUUUCUUU U U ETD02415 2684 AAGAAAAGCA 2866 UCACCGUUCU GAACGGUGAU GCUUUUCUUU U U ETD02416 2684 AAGAAAAGCA 2866 UCACCGUUCU GAACGGUGAU GCUUUUCUUU U U ETD02417 2684 AAGAAAAGCA 2866 UCACCGUUCU GAACGGUGAU GCUUUUCUUU U U ETD02418 2684 AAGAAAAGCA 2866 UCACCGUUCU GAACGGUGAU GCUUUUCUUU U U ETD02419 2684 AAGAAAAGCA 2866 UCACCGUUCU GAACGGUGAU GCUUUUCUUU U U ETD02420 2684 AAGAAAAGCA 2866 UCACCGUUCU GAACGGUGAU GCUUUUCUUU U U ETD02182 2681 UCUACAAAGG 2863 UUGAGUUCAC UGAACUCAAU CUUUGUAGAU U U ETD02459 2681 UCUACAAAGG 2863 UUGAGUUCAC UGAACUCAAU CUUUGUAGAU U U

TABLE 70 Relative MTRES1 mRNA Levels in Livers of Mice Mean MTRES1 mRNA (Normalized Group n Treatment Dose (ug) to Group 1, Day 14) 1 3 PBS 1 2 3 ETD02406 50 0.46 3 3 ETD02409 50 0.27 4 3 ETD02413 50 0.73 5 3 ETD02414 50 0.7 6 3 ETD02415 50 0.48 7 3 ETD02416 50 0.51 8 3 ETD02417 50 0.18 9 3 ETD02418 50 0.31 10 3 ETD02419 50 0.44 11 3 ETD02420 50 0.29 12 3 ETD02182 50 0.22 13 3 ETD02459 50 0.28

Additional siRNAs targeting human MTRES1 mRNA and cross-reactive with at least cynomolgus monkey MTRES1 mRNA were tested for activity in mice following transfection with an adeno-associated viral vector. The siRNAs were attached to the GalNAc ligand ETL17. The siRNA sequences are shown in Table 71, where Nf is a 2′-fluoro-modified nucleoside, n is a 2′-O-methyl modified nucleoside, “d” is a deoxynucleoside, nm is a 2′-O-(2-methoxyethyl) modified nucleoside, and “s” is a phosphorothioate linkage. Base sequences are shown in Table 72.

Six- to eight-week-old female mice (C57Bl/6) were injected with 5 μL of a recombinant adeno-associated virus 8 (AAV8) vector (1.4×10E13 genome copies/mL) by the retroorbital route on Day-14. The recombinant AAV8 contained the open reading frame and the majority of the 3′UTR of the human MTRES1 sequence (NM_016487.5) under the control of the human thyroxine binding globulin promoter in an AAV2 backbone packaged in AAV8 capsid (AAV8-TBG-h-MTRES1). On Day 0, infected mice (n=6-7/group) were given a subcutaneous injection of a single 100 μg dose of a GalNAc-conjugated siRNA or PBS as vehicle control.

Mice were euthanized on Day 14 after subcutaneous injection and a liver sample from each was collected and placed in RNAlater (ThermoFisher Catalog #AM7020) until processing. Total liver RNA was prepared by homogenizing the liver tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer's recommendations. Preparation of cDNA was performed using Quanta qScript cDNA SuperMix (VWR, Catalog #95048-500) according to the manufacturer's instructions. The relative levels of liver MTRES1 mRNA were assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for human MTRES1 (ThermoFisher, assay #Hs01568158_g1) and the mouse housekeeping gene PPIA (ThermoFisher, assay #Mm02342430_g1) and PerfeCTaR qPCR FastMix®, Low ROX™ (VWR, Catalog #101419-222). Data were normalized to the mean MTRES1 mRNA level in animals receiving PBS. Results are shown in Table 73. Mice injected with ETD02373, ETD02409, or ETD02356 had greatest reductions in mean liver MTRES1 mRNA on Day 14 relative to mice receiving PBS.

TABLE 71 Example siRNA Sequences Sense Strand Sequence Anti- Sense (5′-3′) sense Antisense Strand with Strand Strand siRNA SEQ GalNAc SEQ Sequence Name ID NO: moiety ID NO: (5′-3′) ETD02356 3093 [ETL17] 3181 usAfsaGfcA sgcuagUfgU faUfuUfaAf fUfaaauugc cAfcUf uuasusu aGfcsusu ETD02358 3095 [ETL17] 2339 usAfsuCfgA sguacUfUfC fuUfcCfaGf fCfUfggaa gAfaGf ucgauasusu uAfcsusu ETD02360 3097 [ETL17] 2351 usAfsuUfuG saaguUfaCf fgUfgCfaCf gUfgCfacca gUfaAf aauasusu cUfususu ETD02365 3102 [ETL17] 3190 usUfsuCfuC sggcuAfgAf fcCfaAfuAf uAfuuggga uCfuAf gaaasusu gCfcsusu ETD02373 3110 [ETL17] 3198 usAfsgAfgA scaguUfaUf faUfcCfgCf gCfggauucu aUfaAf cuasusu cUfgsusu ETD02409 3306 [ETL17] 3135 [ETL17]sa saagamaAfA agamaAfA fGfCfagaa fGfCfagaa mcggugasus mcggugasus u u ETD02379 3116 [ETL17] 3204 usUfscUfuA sguuuAfaAf fgGfcAfaCf GfdTuGfcc uUfuAf uaagaasusu aAfcsusu

TABLE 72 Example siRNA BASE Sequences Sense Antisense Strand Strand SEQ Base SEQ Base siRNA ID Sequence ID Sequence Name NO: (5′ to 3′) NO: (5′ to 3′) ETD02356 2788 GCUAGUGUUA 2970 UAAGCAAUUU AAUUGCUUAU AACACUAGCU U U ETD02358 2790 GUACUUCCUG 2972 UAUCGAUUCC GAAUCGAUAU AGGAAGUACU U U ETD02360 2792 AAGUUACGUG 2974 UAUUUGGUGC CACCAAAUAU ACGUAACUUU U U ETD02365 2797 GGCUAGAUAU 2979 UUUCUCCCAA UGGGAGAAAU UAUCUAGCCU U U ETD02373 2805 CAGUUAUGCG 2987 UAGAGAAUCC GAUUCUCUAU GCAUAACUGU U U ETD02409 2684 GUUUAAAGUU 2866 UUCUUAGGCA GCCUAAGAAU ACUUUAAACU U U ETD02379 3338 AAGAAAAGCA 2993 UCACCGUUCU GAACGGUGAU GCUUUUCUUU U U

TABLE 73 Relative MTRES1 mRNA Levels in Livers of Mice Mean MTRES1 mRNA (Normalized Group n Treatment Dose (ug) to Group 1, Day 14) 1 7 PBS 1 2 6 ETD02356 100 0.41 3 7 ETD02358 100 0.62 4 7 ETD02360 100 1.01 5 6 ETD02365 100 0.5 6 7 ETD02373 100 0.19 7 6 ETD02409 100 0.2 8 7 ETD02379 100 0.59

The base sequences of ETD02409 were synthesized with alternative modification patterns and then tested for activity in mice. The siRNAs were attached to the GalNAc ligand ETL17. The siRNA sequences are shown in Table 74, where Nf is a 2′-fluoro-modified nucleoside, n is a 2′-O-methyl modified nucleoside, nm is a 2′-O-(2-methoxyethyl) modified nucleoside, and “s” is a phosphorothioate linkage. Base sequences are shown in Table 75.

Six- to eight-week-old female mice (strain ICR, n=3) were given a subcutaneous injection on Day 0 of a single 50 μg dose of a GalNAc-conjugated siRNA or PBS as vehicle control.

Mice were euthanized on Day 14 after injection and a liver sample from each was collected and placed in RNAlater (ThermoFisher Catalog #AM7020) until processing. Total liver RNA was prepared by homogenizing the liver tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer's recommendations. Preparation of cDNA was performed using Quanta qScript cDNA SuperMix (VWR, Catalog #95048-500) according to the manufacturer's instructions. The relative levels of liver MTRES1 mRNA were assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for mouse MTRES1 (ThermoFisher, assay #Mm00471319_m1) and the mouse housekeeping gene PPIA (ThermoFisher, assay #Mm02342430_g1) and PerfeCTa® qPCR FastMix®, Low ROX™ (VWR, Catalog #101419-222). Data were normalized to the mean MTRES1 mRNA level in animals receiving PBS. Results are shown in Table 76. Mice injected with ETD02591, ETD02589, or ETD02588 had greatest reductions in mean liver MTRES1 mRNA on Day 14 relative to mice receiving PBS.

TABLE 74 Example siRNA Sequences Sense Strand Anti- Sequence sense Sense (5′-3′) Strand Antisense Strand with SEQ Strand siRNA SEQ ID GalNAc ID Sequence Name NO: moiety NO: (5′-3′) ETD02587 3306 [ETL17] 3322 usCfsaCfcg saagamaAfA UfucUfgCfu fGfCfagaam UfuUfcUfus cggugasusu usu ETD02588 3306 [ETL17] 3323 usCfsacCfg saagamaAfA UfucUfgCfu fGfCfagaam UfuUfcUfus cggugasusu usu ETD02589 3306 [ETL17] 3324 usCfsacCfg saagamaAfA UfuCfugcuU fGfCfagaam fuUfcUf cggugasusu ususu ETD02590 3306 [ETL17] 3325 usCfsacCfg saagamaAfA UfucUfgcuU fGfCfagaam fuUfcUfusu cggugasusu su ETD02591 3306 [ETL17] 3326 usCfsacCfg saagamaAfA UfucUfgcuU fGfCfagaam fuUfcuusus cggugasusu u ETD02409 3306 [ETL17] 3135 usCfsaCfcG saagamaAfA fuUfcUfgCf fGfCfagaam uUfuUfcUfu cggugasusu susu

TABLE 75 Example siRNA BASE Sequences Sense Antisense Strand Strand Base Base SEQ Sequence SEQ Sequence SiRNA ID (5′ to ID (5′ to Name NO: 3′) NO: 3′) ETD02587 2684 AAGAAAAGCA 2866 UCACCGUUCU GAACGGUGAU GCUUUUCUUU U U ETD02588 2684 AAGAAAAGCA 2866 UCACCGUUCU GAACGGUGAU GCUUUUCUUU U U ETD02589 2684 AAGAAAAGCA 2866 UCACCGUUCU GAACGGUGAU GCUUUUCUUU U U ETD02590 2684 AAGAAAAGCA 2866 UCACCGUUCU GAACGGUGAU GCUUUUCUUU U U ETD02591 2684 AAGAAAAGCA 2866 UCACCGUUCU GAACGGUGAU GCUUUUCUUU U U ETD02409 2684 AAGAAAAGCA 2866 UCACCGUUCU GAACGGUGAU GCUUUUCUUU U U

TABLE 76 Relative MTRES1 mRNA Levels in Livers of Mice Mean MTRES1 mRNA (Normalized Group n Treatment Dose (ug) to Group 1, Day 14) 1 3 PBS 1 2 3 ETD02587 50 0.44 3 3 ETD02588 50 0.36 4 3 ETD02589 50 0.27 5 3 ETD02590 50 0.44 6 3 ETD02591 50 0.21 7 3 ETD02409 50 0.48

The base sequence of ETD02183 was synthesized with alternative modification patterns and then tested for activity in mice. The siRNAs were attached to the GalNAc ligand ETL17. The siRNA sequences are shown in Table 77, where Nf is a 2′-fluoro-modified nucleoside, n is a 2′-O-methyl modified nucleoside, nm is a 2′-O-(2-methoxyethyl) modified nucleoside, and “s” is a phosphorothioate linkage. Base sequences are shown in Table 78.

Six- to eight-week-old female mice (strain ICR, n=3) were given a subcutaneous injection on Day 0 of a single 50 μg dose of a GalNAc-conjugated siRNA or PBS as vehicle control.

Mice were euthanized on Day 14 after injection and a liver sample from each was collected and placed in RNAlater (ThermoFisher Catalog #AM7020) until processing. Total liver RNA was prepared by homogenizing the liver tissue in homogenization buffer (Maxwell RSC simply RNA Tissue Kit) using a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer's recommendations. Preparation of cDNA was performed using Quanta qScript cDNA SuperMix (VWR, Catalog #95048-500) according to the manufacturer's instructions. The relative levels of liver MTRES1 mRNA were assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for mouse MTRES1 (ThermoFisher, assay #Mm00471319_m1) and the mouse housekeeping gene PPIA (ThermoFisher, assay #Mm02342430_g1) and PerfeCTaR qPCR FastMix®, Low ROX™ (VWR, Catalog #101419-222). Data were normalized to the mean MTRES1 mRNA level in animals receiving PBS. Results are shown in Table 79.

TABLE 77 Example siRNA Sequences Sense Strand Anti- Sense Sequence sense Strand (5′-3′) Strand Antisense SEQ with SEQ Strand siRNA ID GalNAc ID Sequence Name NO: moiety NO: (5′-3′) ETD02183 3051 [ETL17] 3143 usUfsgaGfu sucuacAfAf UfcaCfcUfu AfGfGfugaa UfgUfa cucaasus Gfasusu u ETD02581 3307 [ETL17] 3143 usUfsgaGfu sucuamcAfA UfcaCfcUfu fAfGfgug UfgUfa maacucaasu Gfasusu su ETD02582 3308 [ETL17] 3143 usUfsgaGfu sucuamcAfA UfcaCfcUfu fAfGfgugam UfgUfaGfas acucaasusu usu ETD02583 3309 [ETL17] 3143 usUfsgaGfu sucuamcAfA UfcaCfcUfu fAfGfgugaa UfgUfaGfas mcucaasusu usu

TABLE 78 Example siRNA BASE Sequences Sense Antisense Strand Strand Base Base Sequence Sequence SEQ (5′ SEQ (5′ siRNA ID to ID to Name NO: 3′) NO: 3′) ETD02183 3143 UCUACAAAGG 2863 UUGAGUUCAC UGAACUCAAU CUUUGUAGAU U U ETD02581 3143 UCUACAAAGG 2863 UUGAGUUCAC UGAACUCAAU CUUUGUAGAU U U ETD02582 3143 UCUACAAAGG 2863 UUGAGUUCAC UGAACUCAAU CUUUGUAGAU U U ETD02583 3143 UCUACAAAGG 2863 UUGAGUUCAC UGAACUCAAU CUUUGUAGAU U U

TABLE 79 Relative MTRES1 mRNA Levels in Livers of Mice Mean MTRES1 mRNA (Normalized Group n Treatment Dose (ug) to Group 1, Day 14) 1 3 PBS 1 2 3 ETD02183 50 0.25 3 3 ETD02581 50 0.42 4 3 ETD02582 50 0.44 5 3 ETD02583 50 0.32

The base sequence of ETD02548 was synthesized with alternative modification patterns and then tested for activity in mice. The siRNAs were attached to the GalNAc ligand ETL17. The siRNA sequences are shown in Table 80, where Nf is a 2′-fluoro-modified nucleoside, n is a 2′-O-methyl modified nucleoside, nm is a 2′-O-(2-methoxyethyl) modified nucleoside, and “s” is a phosphorothioate linkage. Base sequences are shown in Table 81.

Six- to eight-week-old female mice (strain ICR, n=3) were given a subcutaneous injection on Day 0 of a single 60 μg dose of a GalNAc-conjugated siRNA or PBS as vehicle control. Mice were euthanized on Day 14 after injection and a liver sample from each was collected and placed in RNAlater (ThermoFisher Catalog #AM7020) until processing. Total liver RNA was prepared by homogenizing the liver tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer's recommendations. Preparation of cDNA was performed using Quanta qScript cDNA SuperMix (VWR, Catalog #95048-500) according to the manufacturer's instructions. The relative levels of liver MTRES1 mRNA were assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for mouse MTRES1 (ThermoFisher, assay #Mm00471319_m1) and the mouse housekeeping gene PPIA (ThermoFisher, assay #Mm02342430_g1) and PerfeCTa® qPCR FastMix®, Low ROX™ (VWR, Catalog #101419-222). Data were normalized to the mean MTRES1 mRNA level in animals receiving PBS. Results are shown in Table 82.

TABLE 80 Example siRNA Sequences Sense Strand Anti- Sense Sequence sense Strand (5′-3′) Strand Antisense SEQ with SEQ Strand siRNA ID GalNAc ID Sequence Name NO: moiety NO: (5′-3′) ETD02548 3310 [ETL17] 3328 usAfsccGfu sgaagmaAfA UfcuGfcUfu fAfGfcagam UfuCfuuc acgguasusu susu ETD02763 3311 [ETL17] 3328 usAfsccGfu sgaagmaaAf UfcuGfcUfu AfGfCfagam UfuCfuuc acggu susu asusu ETD02764 3312 [ETL17] 3329 usAfsccGfu sgaagmAfaA UfcuGfcUfu fAfGfCfaga UfuCfuuc macgg susu uasusu ETD02765 3312 [ETL17] 3330 usAfsccgUf sgaagmaAfA UfcuGfcUfu fAfGfcagam UfuCfuuc acggu susu asusu ETD02766 3312 [ETL17] 3331 usAfsccGfu sgaagmaAfA UfCfuGfcuu fAfGfcagam UfuCfuuc acggu susu asusu ETD02767 3306 [ETL17] 3326 usAfsccGfu sgaagmaAfA UfCfugcUfu fAfGfcagam UfuCfuuc acggu susu asusu ETD0259 3051 [ETL17] 3143 usCfsacCfg saagamaAfA UfucUfgcuU fGfCfagaam fuUfcuus cggug usu asusu ETD02183 3312 [ETL17] 3328 usUfsgaGfu sucuacAfAf UfcaCfcUfu AfGfGfugaa UfgUfaGf cucaas asusu usu ETD02181 3051 [ETL17] 3141 usUfsgagUf sucuacAfAf uCfaCfcuuU AfGfGfugaa fgUfaGfa cucaasusu susu

TABLE 81 Example siRNA BASE Sequences Sense Antisense Strand Strand Base Base SEQ Sequence SEQ Sequence siRNA ID (5′ ID (5′ Name NO: to 3′) NO: to 3′) ETD02548 2683 GAAGAAAAGC 2865 UACCGUUCUG AGAACGGUAU CUUUUCUUCU U U ETD02763 2683 GAAGAAAAGC 2865 UACCGUUCUG AGAACGGUAU CUUUUCUUCU U U ETD02764 2683 GAAGAAAAGC 2865 UACCGUUCUG AGAACGGUAU CUUUUCUUCU U U ETD02765 2683 GAAGAAAAGC 2865 UACCGUUCUG AGAACGGUAU CUUUUCUUCU U U ETD02766 2683 GAAGAAAAGC 2865 UACCGUUCUG AGAACGGUAU CUUUUCUUCU U U ETD02767 2684 GAAGAAAAGC 2866 UACCGUUCUG AGAACGGUAU CUUUUCUUCU U U ETD02591 2681 AAGAAAAGCA 2863 UCACCGUUCU GAACGGUGAU GCUUUUCUUU U U ETD02183 2683 UCUACAAAGG 2865 UUGAGUUCAC UGAACUCAAU CUUUGUAGAU U U ETD02181 2681 UCUACAAAGG 2863 UUGAGUUCAC UGAACUCAAU CUUUGUAGAU U U

TABLE 82 Relative MTRES1 mRNA Levels in Livers of Mice Mean MTRES1 mRNA (Normalized Group n Treatment Dose (ug) to Group 1, Day 14) 1 3 PBS 1 2 3 ETD02763 60 0.25 3 3 ETD02764 60 0.29 4 3 ETD02765 60 0.26 5 3 ETD02766 60 0.21 6 3 ETD02767 60 0.22 7 3 ETD02591 60 0.25 8 3 ETD02183 60 0.25 9 3 ETD02548 60 0.19 10 3 ETD02181 60 0.16

The base sequence ETD02591 was synthesized with alternative modification patterns and then tested for activity in mice. The siRNAs were attached to the GalNAc ligand ETL17. The siRNA sequences are shown in Table 83, where Nf is a 2′-fluoro-modified nucleoside, n is a 2′-O-methyl modified nucleoside, [NUNA] is a unlocked nucleic acid, nm is a 2′-O-(2-methoxyethyl) modified nucleoside, “i” is a 2′-O-methyl inosine nucleoside, and “s” is a phosphorothioate linkage. Base sequences are depicted in Table 84.

Six- to eight-week-old female mice (strain ICR, n=3) were given a subcutaneous injection on Day 0 of a single 60 μg dose of a GalNAc-conjugated siRNA or PBS as vehicle control. Mice were euthanized on Day 14 after injection and a liver sample from each was collected and placed in RNAlater (ThermoFisher Catalog #AM7020) until processing. Total liver RNA was prepared by homogenizing the liver tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer's recommendations. Preparation of cDNA was performed using Quanta qScript cDNA SuperMix (VWR, Catalog #95048-500) according to the manufacturer's instructions. The relative levels of liver MTRES1 mRNA were assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for mouse MTRES1 (ThermoFisher, assay #Mm00471319_m1) and the mouse housekeeping gene PPIA (ThermoFisher, assay #Mm02342430_g1) and PerfeCTa® qPCR FastMix®, Low ROX™ (VWR, Catalog #101419-222). Data were normalized to the mean MTRES1 mRNA level in animals receiving PBS. Results are shown in Table 85.

TABLE 83 Example siRNA Sequences Sense Strand Anti- Sense Sequence sense Strand (5′-3′) Strand Antisense SEQ with SEQ Strand siRNA ID GalNAc ID Sequence Name NO: moiety NO: (5′-3′) ETD02591 3306 [ETL17] 3326 usCfsacCfg saagamaAfA UfucUfgcuU fGfCfagaam fuUfcuu oggugasusu susu ETD02756 3313 [ETLI7] 3326 usCfsacCfg saagamaaAf UfucUfgcuU GfCfAfgaam fuUfcuu oggugasusu susu ETD02757 3314 [ETLI7] 3326 usCfsacCfg saagamAfaA UfucUfgcuU fGfCfAfgaa fuUfcuu mcggugasus susu u ETD02758 3306 [ETL17] 3332 usCfsaccGf saagamaAfA UfucUfgcuU fGfCfagaam fuUfcuu cegugasusu susu ETD02759 3306 [ETL17] 3333 usCfsaccgU saagamaAfA fUfcUfgcuU fGfCfagaam fuUfcuu cggugasusu susu ETD02760 3306 [ETL17] 3334 usCfsacCfg saagamaAfA UfUfcUfgcu fGfCfagaam UfuUfcu cggugasusu ususu ETD02894 3306 [ETL17] 3335 usCfsacCfg saagamaAfA [UUNA] fGfCfagaam ucUfgcuUfu cggugasusu Ufcuususu ETD02895 3306 [ETL17] 3336 usCfsacCf[ saagamaAfA GUNA]fucUf fGfCfagaam gcuUf cggugasusu uUfcuususu ETD02906 3315 [ETL17] 3326 usCfsacCfg saagamaAfA UfucUfgcuU fGfCfagaam fuUfcuu cgguiasusu susu ETD02907 3316 [ETL17] 3326 usCfsacCfg saagamaAfA UfucUfgcuU fGfCfagaam fuUfcuu cgiugasusu susu

TABLE 84 Example siRNA BASE Sequences Sense Antisense Strand Strand Base Base SEQ Sequence SEQ Sequence siRNA ID (5′ ID (5′ Name NO: to 3′) NO: to 3′) ETD02591 2684 AAGAAAAGCA 2866 UCACCGUUCU GAACGGUGAU GCUUUUCUUU U U ETD02756 2684 AAGAAAAGCA 2866 UCACCGUUCU GAACGGUGAU GCUUUUCUUU U U ETD02757 2684 AAGAAAAGCA 2866 UCACCGUUCU GAACGGUGAU GCUUUUCUUU U U ETD02758 2684 AAGAAAAGCA 2866 UCACCGUUCU GAACGGUGAU GCUUUUCUUU U U ETD02759 2684 AAGAAAAGCA 2866 UCACCGUUCU GAACGGUGAU GCUUUUCUUU U U ETD02760 2684 AAGAAAAGCA 2866 UCACCGUUCU GAACGGUGAU GCUUUUCUUU U U ETD02894 2684 AAGAAAAGCA 2866 UCACCGUUCU GAACGGUGAU GCUUUUCUUU U U ETD02895 2684 AAGAAAAGCA 2866 UCACCGUUCU GAACGGUGAU GCUUUUCUUU U U ETD02906 2684 AAGAAAAGCA 2866 UCACCGUUCU GAACGGUGAU GCUUUUCUUU U U ETD02907 2684 AAGAAAAGCA 2866 UCACCGUUCU GAACGGUGAU GCUUUUCUUU U U

TABLE 85 Relative MTRES1 mRNA Levels in Livers of Mice Mean MTRES1 mRNA (Normalized Group n Treatment Dose (ug) to Group 1, Day 14) 1 3 PBS 1 2 3 ETD02591 60 0.31 3 3 ETD02756 60 0.18 4 3 ETD02757 60 0.22 5 3 ETD02758 60 0.31 6 3 ETD02759 60 0.38 7 3 ETD02760 60 0.32 8 3 ETD02894 60 0.85 9 3 ETD02895 60 0.64 10 3 ETD02906 60 0.35 11 3 ETD02907 60 0.29

Rats were placed in ventral recumbancy and an incision was made parallel to the midline to expose the L2 spinous process. A pre-made catheter was inserted between L1 and L2, advanced cranially, and secured in place. The external part of the catheter is tunneled subcutaneously, exteriorized, and secured just below the scapular region using wound clips.

−1 Duplexes formulated at 30 mg mlin 0.9% NaCl in water were administered as 30-u1 IT injections in male Sprague Dawley rats (N=5) 250-300 g. siRNA was administered using a sterile tuberculin syringe and 27-gauge needle. Bolus injections of 30 μl were administered over a period of 10-15 seconds. Following injection, the catheter was flushed with 40 μl vehicle. Sequences are depicted in Tables 86-87.

Rats were euthanized on Day 14 after injection and samples of liver, kidney, frontal cortex, hippocampus, brain stem, cerebellum, and the spinal cord from each were collected, flash frozen in liquid nitrogen, and stored at −80° C. until processing. Total RNA was prepared by homogenizing the tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer's recommendations. Preparation of cDNA was performed using Quanta qScript cDNA SuperMix (VWR, Catalog #95048-500) according to the manufacturer's instructions. The relative levels of MTRES1 mRNA were assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for rat MTRES1 (ThermoFisher, assay #Rn01441122_m1) and the rat housekeeping gene PPIA (ThermoFisher, assay #Rn00630933_m1) and PerfeCTa® qPCR FastMix®, Low ROX™ (VWR, Catalog #101419-222). Data were normalized to the mean MTRES1 mRNA level in animals receiving vehicle (saline) control. Results are shown in table below. Rats injected with either ETD02793 or ETD02275 showed a decrease in MTRES1 mRNA compared to rats receiving vehicle in all tissues examined. Results are depicted in Table 88.

TABLE 86 Example siRNA Sequences Sense Strand Anti- Sense Sequence sense Antisense Strand (5′-3′) Strand Strand siRNA SEQ with SEQ Sequence Name ID NO: moiety ID NO: (5′-3′) ETD02793 3296 [ETL20] 3337 5VPusCfsac aagamaAfAf CfgUfucUfg GfCfagaamc cuUfuUfcu g ususu ETD02275 3242 [ETL20] 3248 5VPusAfscc gaagAfAfAf gUfuCfuGfc AfGfcagaac UfuUfuCfuU gguasusu fcsusu

Where 5VP is vinyl phosphonate at 5′ end of antisense strand using 5′-POM-vinyl phosphonate, 2′-OMe-U CE-Phosphoramidite (Biosearch Technologies, 2579).

TABLE 87 Example siRNA BASE Sequences Sense Antisense Strand Strand Base Base SEQ Sequence SEQ Sequence siRNA ID (5′ ID (5′ Name NO: to 3′) NO: to 3′) ETD02793 2684 AAGAAAAGCA 2866 UCACCGUUCU GAACGGUGAU GCUUUUCUUU U U ETD02275 2683 GAAGAAAAGC 2865 UACCGUUCUG AGAACGGUAU CUUUUCUUCU U U

TABLE 88 Relative MTRES1 mRNA Levels in Mouse Tissues vehicle control ETD02793 ETD02275 Relative Relative Relative Tissue mRNA n mRNA n mRNA n Kidney 1 5 0.44 5 0.32 5 Liver 1 5 0.76 5 0.51 5 Lumbar Spinal Cord 1 5 0.49 5 0.18 5 Thoracic Spinal Cord 1 5 0.17 5 0.15 5 Cervical Spinal Cord 1 5 0.25 5 0.18 5 Cerebellum 1 5 0.17 5 0.26 5 Brain Stem 1 5 0.22 5 0.25 5 Hippocampus 1 5 0.14 5 0.23 5 Frontal Cortex 1 5 0.22 5 0.25 5

−1 Duplexes formulated at 30 mg mlin 0.9% NaCl in water were administered as 30-μl IT injections in Sprague Dawley rats (N=5/group) 250-300 g surgically implanted with an intrathecal catheter. siRNA was administered using a sterile Hamilton syringe and 23-gauge needle. Bolus injections of 30 μl were administered over a period of 10-15 seconds. Following injection, the catheter was flushed with 40 μl vehicle Sequences are depicted in Tables 89-90.

Rats were euthanized on Day 14 after injection and samples of liver, kidney, frontal cortex, hippocampus, brain stem, cerebellum, and the spinal cord from each were collected, flash frozen in liquid nitrogen and stored at −80° C. until processing. Total RNA was prepared by homogenizing the tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer's recommendations. Preparation of cDNA was performed using Quanta qScript cDNA SuperMix (VWR, Catalog #95048-500) according to the manufacturer's instructions. The relative levels of MTRES1 mRNA were assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for rat MTRES1 (ThermoFisher, assay #Rn01441122_m1) and the rat housekeeping gene PPIA (ThermoFisher, assay #Rn00630933_m1) and PerfeCTaR qPCR FastMix®, Low ROX™ (VWR, Catalog #101419-222). Data were normalized to the mean MTRES1 mRNA level in animals receiving vehicle (saline) control. Results are shown in table below. Rats injected with either ETD02968, ETD02793, or ETD03000 showed a decrease in MTRES1 mRNA compared to rats receiving vehicle in all CNS tissues examined. Results are depicted in Table 91.

TABLE 89 Example siRNA Sequences Sense Strand Anti- Sense Sequence sense Antisense Strand (5′-3′) Strand Strand siRNA SEQ ID with SEQ ID Sequence Name NO: moiety NO: (5′-3′) ETD02968 3318 asasgamaA( 3337 5VPusCfsac C16)AfGfCf CfgUfucUfg agaamcggug cuUfuUfcuu asusu susu ETD02793 3296 [ETL20] 3337 5VPusCfsac aagamaAfAf CfgUfucUfg GfCfagaamc cuUfuUfcuu ggugasusu susu ETD03000 3317 [ETL20] 3337 5VPusCfsac aagamaaAfG CfgUfucUfg fCfAfgaamc cuUfuUfcuu gg susu

Where 5VP is vinyl phosphonate at 5′ end of antisense strand using 5′-POM-vinyl phosphonate, 2′-OMe-U CE-Phosphoramidite (Biosearch Technologies, 2579) and A(C16) is 2′-O-hexadecyl adenylate.

TABLE 90 Example siRNA BASE Sequences Sense Antisense Strand Strand Base Base SEQ Sequence SEQ Sequence siRNA ID (5′ ID (5′ Name NO: to 3′) NO: to 3′) ETD02968 2684 AAGAAAAGCA 2866 UCACCGUUCU GAACGGUGAU GCUUUUCUUU U U ETD02793 2684 AAGAAAAGCA 2866 UCACCGUUCU GAACGGUGAU GCUUUUCUUU U U ETD03000 2684 AAGAAAAGCA 2866 UCACCGUUCU GAACGGUGAU GCUUUUCUUU U U

TABLE 91 Relative MTRES1 mRNA Levels in Rat Tissues Vehicle Control ETD02968 ETD02793 ETD03000 Relative Relative Relative Relative Tissue mRNA n mRNA n mRNA n mRNA n Kidney 1 5 0.96 5 0.48 5 0.24 5 Liver 1 5 0.49 5 0.9 5 0.67 5 Lumbar Spinal Cord 1 5 0.15 5 0.13 5 0.1 5 Thoracic Spinal Cord 1 5 0.09 5 0.17 5 0.13 5 Cervical Spinal Cord 1 5 0.11 5 0.18 5 0.18 5 Cerebellum 1 5 0.4 5 0.13 5 0.11 5 Brain Stem 1 5 0.21 5 0.14 5 0.16 5 Hippocampus 1 5 0.25 5 0.14 5 0.11 5 Frontal Cortex 1 5 0.5 5 0.18 5 0.18 5

Four groups of four male cynomolgus monkeys >3 years old were utilized for this study. Monkeys were maintained on normal chow with ad libitum access throughout the study except prior to blood collections in which they were fasted overnight (at least 12 hours). On study Day 0, cynomolgus monkeys were injected subcutaneously (2 mL/kg) with a single dose of 3 mg/kg ETD02183, ETD02189, ETD02591, and ETD02373 at a concentration of 1.5 mg/mL. The sequence of the siRNAs used are shown in Table 92, where Nf (e.g. Af, Cf, Gf, Tf, or Uf) is a 2′-fluoro-modified nucleoside, n (e.g. a, c, g, t, or u) is a 2′-O-methyl modified nucleoside, and “s” is a phosphorothioate linkage. The base sequences for each siRNA are shown in Table 93.

TABLE 92 Example siRNA Sequence Sense Strand Sequence Antisense SEQ (5′-3′) with SEQ Strand ID GalNAc ID Sequence ETD# NO: moiety NO: (5′-3′) ETD02183 3051 [ETL17]sucua 3143 usUfsgaGfuU cAfAfAfGfGfu fcaCfcUfuUf gaacucaasusu gUfaGfasusu ETD02189 3060 [ETL17]sgaag 3150 usAfsccgUfu AfAfAfAfGfca CfuGfcUfuUf gaacgguasusu uCfuUfcsusu ETD02591 3306 [ETL 17]saag 3326 usCfsacCfgU amaAfAfGfCfa fucUfgcuUfu gaamcggugasu Ufcuususu su ETD02373 3110 [ETL17]scagu 3198 usAfsgAfgAf UfaUfgCfggau aUfcCfgCfaU ucucuasusu faAfcUfgsus u

TABLE 93 Example siRNA BASE Sequence SEQ Sense Strand SEQ Antisense Strand siRNA ID Base Sequence ID Base Sequence Name NO: (5′ to 3′) NO: (5′ to 3′) ETD02183 2681 UCUACAAAGGU 2863 UUGAGUUCACC GAACUCAAUU UUUGUAGAUU ETD02189 2683 GAAGAAAAGCA 2865 UACCGUUCUGC GAACGGUAUU UUUUCUUCUU ETD02591 2684 AAGAAAAGCAG 2866 UCACCGUUCUG AACGGUGAUU CUUUUCUUUU ETD02373 2805 CAGUUAUGCGG 2987 UAGAGAAUCCG AUUCUCUAUU CAUAACUGUU

Body weights were recorded weekly on Days −8, −2, 7, 14, 21, and 28 of the study. On study Days −8, −2, 7, 14, 21, 28, and 56 whole blood was collected into tubes with no anti-coagulant and centrifuged to obtain serum after clotting. Clinical chemistry for ALT, AST, ALP, DBIL, TBIL, GLU, UREA, CREA, TG, CHOL, TP, GGT, HDL-CH, LDL-CH, and B-HDBH were analyzed.

On study Day-8, Day 28, and Day 56 a 5 mg liver biopsy was collected by anesthetizing the animals with Zoletil (1.5-5.0 mg/kg, i.m.) and xylazine (0.5-2.0 mg/kg, i.m.). The liver biopsy was then placed into 10 v/v RNAlater™ Stabilization Solution (Thermo Fisher, Catalog #AM7020) in 20 seconds and stored for 24 hours at 4° C. The RNAlater was then removed, and the liver tissue was stored in the freezer until they were shipped to Empirico.

Total liver RNA was prepared by homogenizing the RNAlater liver tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer's recommendations. Preparation of cDNA was performed using Quanta qScript cDNA SuperMix (VWR, Catalog #95048-500) according to the manufacturer's instructions. The levels of liver MTRES1 mRNA were assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for monkey MTRES1 (Custom Taqman primers and probe: Primer 1 GAT GCA TTC TAC AAA GGT CAA CTC, Primer 2 CTG TCT CTG TTC CTG CTT CTT, Probe/56-FAM/AA GCA GAA C/ZEN/G GTG AAA GTG GGA GA/3IABKFQ/), and the monkey housekeeping gene GUSB (ThermoFisher, assay #Mf04392546_g1) using PerfeCTa® qPCR FastMix®, Low ROX™ (VWR, Catalog #101419-222).

The results of the liver biopsy mRNA analysis are summarized in Table 94. Data for individual animals was normalized to its Day-8 liver biopsy mRNA levels using the delta-delta Ct method. No reduction in liver MTRES1 mRNA was observed with a single dose of ETD02183. A 65% mean reduction in liver MTRES1 mRNA was observed with a single dose of ETD02189 at Day 28 after injection and a 26% mean reduction at Day 56. A 79% mean reduction in liver MTRES1 mRNA was observed with a single dose of ETD02591 and 66% reduction at Day 56. A 37% reduction in liver MTRES1 mRNA was observed with a single dose of ETD02373 and a 13% reduction at Day 56.

There were no significant changes in body weight or any of the clinical chemistry parameters measured during this study.

TABLE 94 MTRES1 Liver mRNA Levels in Monkeys Treated with ETD02183, ETD02189, ETD02591, and ETD02373 Mean Mean Mean Relative Relative Relative Relative Relative Relative Liver Liver Liver Liver Liver Liver MTRES1 MTRES1 MTRES1 MTRES1 MTRES1 MTRES1 mRNA mRNA mRNA mRNA mRNA mRNA Level Level Level Level Level Level Treatment Animal # (Day −8) (Day −8) (Day 28) (Day 28) (Day 56) (Day 56) ETD02183 101 1 1 1.62 1.44 2.32 1.68 102 1 1.74 1.75 103 1 1.26 1.6 104 1 1.14 1.03 ETD02189 201 1 1 0.37 0.35 0.82 0.74 202 1 0.37 0.82 203 1 0.33 0.5 204 1 0.34 0.8 ETD02591 301 1 1 0.27 0.21 0.24 0.34 302 1 0.2 0.31 303 1 0.17 0.44 304 1 0.2 0.38 ETD02373 401 1 1 0.43 0.63 0.7 0.87 402 1 0.81 0.93 403 1 0.71 1.08 404 1 0.58 0.77

−1 −1 The siRNA sequences are shown in Tables 95-96, where Nf is a 2′ fluoro-modified nucleoside, n is a 2′-O-methyl modified nucleoside, nm is a 2′-O-(2-methoxyethyl) modified nucleoside (MOE), “s” is a phosphorothioate linkage and 5VP is vinyl phosphonate at the 5′ end of antisense strand using 5′-POM-vinyl phosphonate, 2′-OMe-U CE-Phosphoramidite (Biosearch Technologies, 2579). Duplexes were formulated at 2.3 mg mland 10 mg mlin 0.9% NaCl in water.

Animals were anesthetized by isoflurane to effect on Day 0 (dosing day), and then doses of test material were administered by intrathecal injection to the lumbar spine at the L4-L5 or L5-L6 intravertebral space. Syringes were loaded individually prior to each dose with 30 μL of dosing solution per animal. The test material at a dose volume of 30 μL/animal was delivered manually, using an insulin syringe with a 28-30-gauge needle. The tip of the needle was introduced into the lumbar spine, and proper insertion of the needle was confirmed by tail flick reflex. Test material was delivered manually over one to two seconds. After injecting the total dose volume, the needle was allowed to stay in place for a minimum of 5 seconds to avoid efflux of the test material to periphery. Animals were placed on a circulating water heating pad until fully recovered from anesthesia.

Rats were euthanized on Day 14 after injection and samples of liver, kidney, frontal cortex, hippocampus, temporal cortex, brain stem, cerebellum, and the spinal cord from each were collected, flash frozen in liquid nitrogen and stored at −80° C. until processing. Total RNA was prepared by homogenizing the tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer's recommendations. Preparation of cDNA was performed using Quanta qScript cDNA SuperMix (VWR, Catalog #95048-500) according to the manufacturer's instructions. The relative levels of MTRES1 mRNA were assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for rat MTRES1 (ThermoFisher, assay #Rn01441122_m1) and the rat housekeeping gene PPIA (ThermoFisher, assay #Rn00630933_m1) and PerfeCTa® qPCR FastMix®, Low ROX™ (VWR, Catalog #101419-222). Data were normalized to the mean MTRES1 mRNA level in animals receiving vehicle (saline) control. Results are shown in Table 97 below.

Animal health checks were performed at least once daily to check for general health, mortality and moribundity. No treatment related observations were noted. There was no difference in body weight in treatment groups compared to the vehicle treated group and all animals body weight increased over the course of the study (not shown).

TABLE 95 Example siRNA Sequence Sense Anti- Sense Strand sense Strand Sequence Strand Antisense SEQ (5′-3′) SEQ Strand siRNA ID with ID Sequence Name NO: moiety NO: (5′-3′) ETD02275 3242 [ETL20]gaa 3248 5VPusAfsccg gAfAfAfAfG UfuCfuGfcUf fcagaacggu uUfuCfuUfcs asusu usu ETD02793 3296 [ETL20]aag 3337 5VPusCfsacC amaAfAfGfC fgUfueUfgcu fagaamcggu UfuUfcuusus gasusu u ETD03000 3317 [ETL20]aag 3337 5VPusCfsacCf amaaAfGfCf gUfucUfgcuUf Afgaamcggu uUfcuususu gasusu

TABLE 96 Example siRNA BASE Sequence SEQ Antisense SEQ Sense Strand ID Strand Base siRNA ID Base Sequence Sequence Name NO: (5′ to 3′) NO: (5′ to 3′) ETD02275 2683 GAAGAAAAGCA 2865 UACCGUUCUGC GAACGGUAUU UUUUCUUCUU ETD02793 2684 AAGAAAAGCA 2866 UCACCGUUCUG GAACGGUGAUU CUUUUCUUUU ETD03000 2684 AAGAAAAGCA 2866 UCACCGUUCU GAACGGUGAUU GCUUUUUUUU

TABLE 97 Relative MTRES1 mRNA Levels in Rat Tissues vehicle ETD02275 ETD02793 ETD03000 control Dose Dose Dose Relative 70 μg 300 μg 70 μg 300 μg 70 μg 300 μg Tissue mRNA Relative mRNA Relative mRNA Relative mRNA Kidney 1 0.87 0.69 0.84 0.77 0.89 0.68 Liver 1 1.3 0.92 1.1 1.12 1.05 1.06 Lumbar Spinal Cord 1 0.3 0.14 0.18 0.17 0.19 0.19 Thoracic Spinal Cord 1 0.35 0.17 0.22 0.17 0.25 0.17 Cervical Spinal Cord 1 0.61 0.25 0.29 0.26 0.27 0.2 Cerebellum 1 0.53 0.32 0.29 0.17 0.35 0.31 Brain Stem 1 0.5 0.23 0.3 0.2 0.24 0.17 Temporal Cortex 1 0.57 0.27 0.38 0.25 0.32 0.19 Hippocampus 1 0.77 0.39 0.36 0.31 0.27 0.27 Frontal Cortex 1 0.71 0.38 0.43 0.26 0.56 0.23

−1 The siRNA sequences are shown in Tables 98-99, where Nf is a 2′-fluoro-modified nucleoside, n is a 2′-O-methyl modified nucleoside, nm is a 2′-O-(2-methoxyethyl) modified nucleoside, “'s” is a phosphorothioate linkage and 5VP is vinyl phosphonate at the 5′ end of antisense strand using 5′-POM-vinyl phosphonate, 2′-OMe-U CE-Phosphoramidite (Biosearch Technologies, 2579). Duplexes formulated at 30 mg mlin artificial cerebrospinal fluid (aCSF) were administered as 30-μl IT injections in female Sprague Dawley rats (N=3-5/group) 250-300 g surgically implanted with an intrathecal catheter. siRNA was administered using a sterile Hamilton syringe and 23-gauge needle. Bolus injections of 30 μl were administered over a period of 10-15 seconds. Following injection, the catheter was flushed with 40 μl vehicle.

Rats were euthanized on Day 14 after injection and samples of liver, kidney, frontal cortex, hippocampus, brain stem, cerebellum, and the spinal cord from each were collected, flash frozen in liquid nitrogen and stored at −80° C. until processing. Total RNA was prepared by homogenizing the tissue in homogenization buffer (Maxwell RSC simplyRNA Tissue Kit) using a Percellys 24 tissue homogenizer (Bertin Instruments) set at 5000 rpm for two 10 second cycles. Total RNA from the lysate was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer's recommendations. Preparation of cDNA was performed using Quanta qScript cDNA SuperMix (VWR, Catalog #95048-500) according to the manufacturer's instructions. The relative levels of MTRES1 mRNA were assessed by RT-qPCR in triplicate on a QuantStudio™ 6 Pro Real-Time PCR System using TaqMan assays for rat MTRES1 (ThermoFisher, assay #Rn01441122_m1) and the rat housekeeping gene PPIA (ThermoFisher, assay #Rn00630933_m1) and PerfeCTa® qPCR FastMix®, Low ROX™ (VWR, Catalog #101419-222). Data were normalized to the mean MTRES1 mRNA level in animals receiving vehicle control. Results are shown in Table 100 below.

TABLE 98 Example siRNA Sequence Sense Anti- Strand sense Sense Sequence Strand Antisense Strand (5′-3′) SEQ Strand SIRNA SEQ ID with ID Sequence Name NO: moiety NO: (5′-3′) ETD02275 3242 [ETL20]ga 3248 5VPusAfsccg agAfAfAfA UfuCfuGfcUf fGfcagaac uUfuCfuUfcs gguasusu usu ETD03002 3339 [ETL20]ga 3340 5VPusAfsccG agmaAfAfA fuUfcuGfcUf fGfcagama uUfuCfuucsu ccguasusu su ETD02793 3296 [ETL20]aa 3337 5VPusCfsacC gamaAfAfG fgUfucUfgcu fCfagaamc UfuUfcuusus ggugasusu u ETD03000 3317 [ETL20]aa 3337 5VPusCfsacC gamaaAfGf fgUfucUfgcu CfAfgaamc UfuUfcuususu ggugasusu

TABLE 99 Example siRNA BASE Sequence Antisense Strand SEQ Sense Strand SEQ Base SIRNA ID Base Sequence ID Sequence Name NO: (5′ to 3′) NO: (5′ to 3′) ETD02275 2683 GAAGAAAAGCA 2865 UACCGUUCUG GAACGGUAUU CUUUUCUUCU U ETD03002 2683 GAAGAAAAGCA 2865 UACCGUUCUG GAACGGUAUU CUUUUCUUCU U ETD02793 2684 AAGAAAAGCAG 2866 UCACCGUUCU AACGGUGAUU GCUUUUCUUU U ETD03000 2684 AAGAAAAGCA 2866 UCACCGUUCU GAACGGUGAU GCUUUUCUUU U U

TABLE 100 Relative MTRES1 mRNA Levels in Rat Tissues vehicle control ETD02275 ETD03002 ETD02793 ETD03000 Relative Relative Relative Relative Relative Tissue mRNA n mRNA n mRNA n mRNA n mRNA n Kidney 1 4 0.44 5 0.41 4 0.46 4 0.53 3 Liver 1 4 0.57 5 0.64 4 1.02 4 0.99 3 Lumbar Spinal Cord 1 4 0.11 5 0.14 4 0.24 4 0.24 3 Thoracic Spinal Cord 1 4 0.15 5 0.17 4 0.23 4 0.26 3 Cervical Spinal Cord 1 4 0.24 5 0.25 4 0.26 4 0.44 3 Brain Stem 1 4 0.32 5 0.37 4 0.19 4 0.21 3 Cerebellum 1 4 0.24 5 0.31 4 0.18 4 0.23 3 Hippocampus 1 4 0.33 5 0.34 4 0.23 4 0.34 3 Frontal Cortex 1 4 0.3 5 0.4 4 0.21 4 0.28 3

In this experiment, a mouse model of Alzheimer's Disease (AD) will be used to evaluate effects of the siRNAs described herein that target MTRES1. In some embodiments, the siRNA comprises one or more of SEQ ID NOS: 2675, 2677-2686, 2689, 2720, 2729, 2739, 2745, 2748, 2749, 2754, 2758-2762, 2766, 2767, 2769, 2770, 2786, 2787-2812, 2814-2816, 2819-2822, 2824, 2828-2833, 2836, 2838, 2839, 2857, 2859-2868, 2871, 2873, 2874, 2877-2879, 2940-2944, 2948-2952, 2968-2994, 2996-2998, 3001-3004, 3006, 3010, 3011, 3013-3015, 3018, and 3020. The model includes Tg2576 mice which express human amyloid beta precursor protein (APP) and presenilin-1 (PSEN1) transgenes with five AD-linked mutations. Cognitive function is measured using a forced swimming test (FST).

Seven-month-old mice are divided into two groups: Group 1-a group treated with the siRNA targeting MTRES1, Group 2-a group treated with vehicle.

Mice are administered the siRNA or the vehicle on day 0 of treatment. Every other week thereafter animals from each group will be dosed for a total of 4 injections. The behavioral tests are performed 24 hours after the final injection.

To rule out nonspecific motor effects that could influence the FST results, the potential effect of treatment on locomotor activity is assessed. Mice are evaluated using the openfield paradigm (44×44×40 cm) in a sound-attenuated room. The total distance (cm) traveled by each mouse is recorded for 5 min by a video surveillance system (SMART; Panlab SL, Barcelona, Spain) and is used to quantify activity levels. The floor of the open-field apparatus is cleaned with 10% ethanol between tests.

The FST includes a behavioral test useful for screening potential drugs that influence cognition and assessing other manipulations that are expected to affect cognitive related behaviors. On the first day, mice are placed individually in the water and allowed to swim for 15 min. The next day, mice are placed again in the water to observe the duration of immobility for 6 min using a camera. Following a 1-min session of acclimation to the apparatus, all behaviors are recorded for 5 min by a video surveillance system (SMART 2.5.21; Panlab SL). Immobility is defined as motionless floating in the water, only allowing movements necessary for the animal to keep its head above the water. The total immobility time in the FST is recorded as an index of cognitive ability.

Twenty four hours after the behavioral assessment, the mice are sacrificed by cervical dislocation following an intraperitoneal injection of 0.3 ml Nembutal (5 mg/ml) (Sigma Cat. No. 1507002). Brain and spinal cord tissues are removed and placed in RNAlater for mRNA isolation.

While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and compositions within the scope of these claims and their equivalents be covered thereby.

Some embodiments include one or more nucleic acid sequences in the following tables:

TABLE 101 Sequence Information SEQ ID NO: Description   1-1140 MTRES1 siRNA sense strand sequences 1141-2280 MTRES1 siRNA antisense strand sequences 2281-2334 Modified MTRES1 siRNA sense strand sequences 2335-2388 Modified MTRES1 siRNA antisense strand sequences 2389-2442 Alternatively modified MTRES1 siRNA sense strand sequences 2443 Full-length human MTRES1 mRNA sequence (Ensembl Acc. ENST00000311381.8) (human RNA) 2444-2452 Modification pattern 1S to 9S 2453-2460 Modification pattern 1AS to 8AS 2461 Modification pattern ASO1 2462 Full-length human MTRES1 mRNA sequence (Ensembl Acc. ENST00000625458.1) (human RNA) 2463-2466 Example modified siRNA sense strand sequences 2467-2470 Example modified siRNA antisense strand sequences 2471-2487 Example modified siRNA sense strand sequences 2488-2504 Example modified siRNA antisense strand sequences 2505-2514 Example modified siRNA sense strand sequences 2515-2524 Example modified siRNA antisense strand sequences 2525-2547 Modification pattern 10S to 32S 2549-2549 Modification pattern 9AS to 10AS 2550-2611 Example siRNA sense strand sequences 2612-2673 Example siRNA antisense strand sequences 2674-2855 MTRES1 siRNA sense strand sequences 2856-3037 MTRES1 siRNA antisense strand sequences 3038-3124 Modified MTRES1 siRNA sense strand sequences 3125-3212 Modified MTRES1 siRNA antisense strand sequences 3213-3226 Modification pattern 33S-47S 3227-3238 Modification pattern 11AS-22AS 3239 Modified MTRES siRNA sense sequence 3240 Modification pattern 48S 3241-3242 Modified MTRES siRNA sense sequence 3243-3250 Modified MTRES siRNA antisense sequences 3251-3253 Modification patterns 49S-51S 3254-3258 Modification patterns 23AS-27AS 3259-3260 Modified MTRES siRNA sense sequences 3261-3262 Modified MTRES siRNA antisense sequences 3263-3264 MTRES1 siRNA sense strand sequences 3265-3266 MTRES1 siRNA antisense strand sequences 3267-3273 Modified MTRES siRNA sense sequences 3274-3280 Modified MTRES siRNA antisense sequences 3291-3287 MTRES1 siRNA sense strand sequences 3288-3295 MTRES1 siRNA antisense strand sequences 3296-3299 Modified MTRES siRNA sense sequences 3300-3304 Modified MTRES siRNA antisense sequences

TABLE 102 Sequences SEQ sense strand SEQ antisense strand siRNA ID sequence ID sequence Name NO: (5′-3′) NO: (5′-3′) siRNA 1 1 GCGCAGAUAGGGGUAGCCU 1141 AGGCUACCCCUAUCUGCGC siRNA 2 2 CGCAGAUAGGGGUAGCCUG 1142 CAGGCUACCCCUAUCUGCG siRNA 3 3 GCAGAUAGGGGUAGCCUGG 1143 CCAGGCUACCCCUAUCUGC   siRNA 4 4 CAGAUAGGGGUAGCCUGGA 1144 UCCAGGCUACCCCUAUCUG siRNA 5 5 AGAUAGGGGUAGCCUGGAG 1145 CUCCAGGCUACCCCUAUCU siRNA 6 6 GAUAGGGGUAGCCUGGAGG 1146 CCUCCAGGCUACCCCUAUC siRNA 7 7 AUAGGGGUAGCCUGGAGGC 1147 GCCUCCAGGCUACCCCUAU siRNA 8 8 UAGGGGUAGCCUGGAGGCC 1148 GGCCUCCAGGCUACCCCUA siRNA 9 9 AGGGGUAGCCUGGAGGCCU 1149 AGGCCUCCAGGCUACCCCU siRNA 10 10 GGGGUAGCCUGGAGGCCUG 1150 CAGGCCUCCAGGCUACCCC siRNA 11 11 GGGUAGCCUGGAGGCCUGC 1151 GCAGGCCUCCAGGCUACCC siRNA 12 12 GGUAGCCUGGAGGCCUGCA 1152 UGCAGGCCUCCAGGCUACC siRNA 13 13 GUAGCCUGGAGGCCUGCAG 1153 CUGCAGGCCUCCAGGCUAC siRNA 14 14 UAGCCUGGAGGCCUGCAGU 1154 ACUGCAGGCCUCCAGGCUA siRNA 15 15 AGCCUGGAGGCCUGCAGUC 1155 GACUGCAGGCCUCCAGGCU siRNA 16 16 GCCUGGAGGCCUGCAGUCC 1156 GGACUGCAGGCCUCCAGGC siRNA 17 17 CCUGGAGGCCUGCAGUCCG 1157 CGGACUGCAGGCCUCCAGG siRNA 18 18 CUGGAGGCCUGCAGUCCGC 1158 GCGGACUGCAGGCCUCCAG siRNA 19 19 UGGAGGCCUGCAGUCCGCG 1159 CGCGGACUGCAGGCCUCCA siRNA 20 20 GGAGGCCUGCAGUCCGCGC 1160 GCGCGGACUGCAGGCCUCC siRNA 21 21 GAGGCCUGCAGUCCGCGCG 1161 CGCGCGGACUGCAGGCCUC siRNA 22 22 AGGCCUGCAGUCCGCGCGG 1162 CCGCGCGGACUGCAGGCCU siRNA 23 23 GGCCUGCAGUCCGCGCGGC 1163 GCCGCGCGGACUGCAGGCC siRNA 24 24 GCCUGCAGUCCGCGCGGCC 1164 GGCCGCGCGGACUGCAGGC siRNA 25 25 CCUGCAGUCCGCGCGGCCG 1165 CGGCCGCGCGGACUGCAGG siRNA 26 26 CUGCAGUCCGCGCGGCCGC 1166 GCGGCCGCGCGGACUGCAG siRNA 27 27 UGCAGUCCGCGCGGCCGCG 1167 CGCGGCCGCGCGGACUGCA siRNA 28 28 GCAGUCCGCGCGGCCGCGG 1168 CCGCGGCCGCGCGGACUGC siRNA 29 29 CAGUCCGCGCGGCCGCGGG 1169 CCCGCGGCCGCGCGGACUG siRNA 30 30 AGUCCGCGCGGCCGCGGGG 1170 CCCCGCGGCCGCGCGGACU siRNA 31 31 GUCCGCGCGGCCGCGGGGA 1171 UCCCCGCGGCCGCGCGGAC siRNA 32 32 UCCGCGCGGCCGCGGGGAG 1172 CUCCCCGCGGCCGCGCGGA siRNA 33 33 CCGCGCGGCCGCGGGGAGG 1173 CCUCCCCGCGGCCGCGCGG siRNA 34 34 CGCGCGGCCGCGGGGAGGG 1174 CCCUCCCCGCGGCCGCGCG siRNA 35 35 GCGCGGCCGCGGGGAGGGA 1175 UCCCUCCCCGCGGCCGCGC siRNA 36 36 CGCGGCCGCGGGGAGGGAC 1176 GUCCCUCCCCGCGGCCGCG siRNA 37 37 GCGGCCGCGGGGAGGGACG 1177 CGUCCCUCCCCGCGGCCGC siRNA 38 38 CGGCCGCGGGGAGGGACGA 1178 UCGUCCCUCCCCGCGGCCG siRNA 39 39 GGCCGCGGGGAGGGACGAG 1179 CUCGUCCCUCCCCGCGGCC siRNA 40 40 GCCGCGGGGAGGGACGAGA 1180 UCUCGUCCCUCCCCGCGGC siRNA 41 41 CCGCGGGGAGGGACGAGAG 1181 CUCUCGUCCCUCCCCGCGG siRNA 42 42 CGCGGGGAGGGACGAGAGG 1182 CCUCUCGUCCCUCCCCGCG siRNA 43 43 GCGGGGAGGGACGAGAGGG 1183 CCCUCUCGUCCCUCCCCGC siRNA 44 44 CGGGGAGGGACGAGAGGGC 1184 GCCCUCUCGUCCCUCCCCG siRNA 45 45 GGGGAGGGACGAGAGGGCC 1185 GGCCCUCUCGUCCCUCCCC siRNA 46 46 GGGAGGGACGAGAGGGCCU 1186 AGGCCCUCUCGUCCCUCCC siRNA 47 47 GGAGGGACGAGAGGGCCUG 1187 CAGGCCCUCUCGUCCCUCC siRNA 48 48 GAGGGACGAGAGGGCCUGA 1188 UCAGGCCCUCUCGUCCCUC siRNA 49 49 AGGGACGAGAGGGCCUGAC 1189 GUCAGGCCCUCUCGUCCCU siRNA 50 50 GGGACGAGAGGGCCUGACG 1190 CGUCAGGCCCUCUCGUCCC siRNA 51 51 GGACGAGAGGGCCUGACGU 1191 ACGUCAGGCCCUCUCGUCC siRNA 52 52 GACGAGAGGGCCUGACGUA 1192 UACGUCAGGCCCUCUCGUC siRNA 53 53 ACGAGAGGGCCUGACGUAC 1193 GUACGUCAGGCCCUCUCGU siRNA 54 54 CGAGAGGGCCUGACGUACA 1194 UGUACGUCAGGCCCUCUCG SIRNA 55 55 GAGAGGGCCUGACGUACAG 1195 CUGUACGUCAGGCCCUCUC siRNA 56 56 AGAGGGCCUGACGUACAGA 1196 UCUGUACGUCAGGCCCUCU siRNA 57 57 GAGGGCCUGACGUACAGAU 1197 AUCUGUACGUCAGGCCCUC siRNA 58 58 AGGGCCUGACGUACAGAUU 1198 AAUCUGUACGUCAGGCCCU siRNA 59 59 GGGCCUGACGUACAGAUUA 1199 UAAUCUGUACGUCAGGCCC siRNA 60 60 GGCCUGACGUACAGAUUAU 1200 AUAAUCUGUACGUCAGGCC siRNA 61 61 GCCUGACGUACAGAUUAUA 1201 UAUAAUCUGUACGUCAGGC siRNA 62 62 CCUGACGUACAGAUUAUAA 1202 UUAUAAUCUGUACGUCAGG siRNA 63 63 CUGACGUACAGAUUAUAAG 1203 CUUAUAAUCUGUACGUCAG siRNA 64 64 UGACGUACAGAUUAUAAGC 1204 GCUUAUAAUCUGUACGUCA siRNA 65 65 GACGUACAGAUUAUAAGCG 1205 CGCUUAUAAUCUGUACGUC siRNA 66 66 ACGUACAGAUUAUAAGCGC 1206 GCGCUUAUAAUCUGUACGU siRNA 67 67 CGUACAGAUUAUAAGCGCC 1207 GGCGCUUAUAAUCUGUACG siRNA 68 68 GUACAGAUUAUAAGCGCCA 1208 UGGCGCUUAUAAUCUGUAC siRNA 69 69 UACAGAUUAUAAGCGCCAU 1209 AUGGCGCUUAUAAUCUGUA siRNA 70 70 ACAGAUUAUAAGCGCCAUG 1210 CAUGGCGCUUAUAAUCUGU siRNA 71 71 CAGAUUAUAAGCGCCAUGG 1211 CCAUGGCGCUUAUAAUCUG siRNA 72 72 AGAUUAUAAGCGCCAUGGC 1212 GCCAUGGCGCUUAUAAUCU siRNA 73 73 GAUUAUAAGCGCCAUGGCU 1213 AGCCAUGGCGCUUAUAAUC siRNA 74 74 AUUAUAAGCGCCAUGGCUA 1214 UAGCCAUGGCGCUUAUAAU siRNA 75 75 UUAUAAGCGCCAUGGCUAU 1215 AUAGCCAUGGCGCUUAUAA siRNA 76 76 UAUAAGCGCCAUGGCUAUG 1216 CAUAGCCAUGGCGCUUAUA siRNA 77 77 AUAAGCGCCAUGGCUAUGG 1217 CCAUAGCCAUGGCGCUUAU siRNA 78 78 UAAGCGCCAUGGCUAUGGC 1218 GCCAUAGCCAUGGCGCUUA siRNA 79 79 AAGCGCCAUGGCUAUGGCU 1219 AGCCAUAGCCAUGGCGCUU siRNA 80 80 AGCGCCAUGGCUAUGGCUA 1220 UAGCCAUAGCCAUGGCGCU siRNA 81 81 GCGCCAUGGCUAUGGCUAG 1221 CUAGCCAUAGCCAUGGCGC siRNA 82 82 CGCCAUGGCUAUGGCUAGU 1222 ACUAGCCAUAGCCAUGGCG siRNA 83 83 GCCAUGGCUAUGGCUAGUG 1223 CACUAGCCAUAGCCAUGGC siRNA 84 84 CCAUGGCUAUGGCUAGUGU 1224 ACACUAGCCAUAGCCAUGG siRNA 85 85 CAUGGCUAUGGCUAGUGUU 1225 AACACUAGCCAUAGCCAUG siRNA 86 86 AUGGCUAUGGCUAGUGUUA 1226 UAACACUAGCCAUAGCCAU siRNA 87 87 UGGCUAUGGCUAGUGUUAA 1227 UUAACACUAGCCAUAGCCA siRNA 88 88 GGCUAUGGCUAGUGUUAAA 1228 UUUAACACUAGCCAUAGCC siRNA 89 89 GCUAUGGCUAGUGUUAAAU 1229 AUUUAACACUAGCCAUAGC siRNA 90 90 CUAUGGCUAGUGUUAAAUU 1230 AAUUUAACACUAGCCAUAG siRNA 91 91 UAUGGCUAGUGUUAAAUUG 1231 CAAUUUAACACUAGCCAUA siRNA 92 92 AUGGCUAGUGUUAAAUUGC 1232 GCAAUUUAACACUAGCCAU siRNA 93 93 UGGCUAGUGUUAAAUUGCU 1233 AGCAAUUUAACACUAGCCA siRNA 94 94 GGCUAGUGUUAAAUUGCUU 1234 AAGCAAUUUAACACUAGCC siRNA 95 95 GCUAGUGUUAAAUUGCUUG 1235 CAAGCAAUUUAACACUAGC siRNA 96 96 CUAGUGUUAAAUUGCUUGC 1236 GCAAGCAAUUUAACACUAG siRNA 97 97 UAGUGUUAAAUUGCUUGCC 1237 GGCAAGCAAUUUAACACUA siRNA 98 98 AGUGUUAAAUUGCUUGCCG 1238 CGGCAAGCAAUUUAACACU siRNA 99 99 GUGUUAAAUUGCUUGCCGG 1239 CCGGCAAGCAAUUUAACAC siRNA 100 100 UGUUAAAUUGCUUGCCGGU 1240 ACCGGCAAGCAAUUUAACA siRNA 101 101 GUUAAAUUGCUUGCCGGUG 1241 CACCGGCAAGCAAUUUAAC siRNA 102 102 UUAAAUUGCUUGCCGGUGU 1242 ACACCGGCAAGCAAUUUAA siRNA 103 103 UAAAUUGCUUGCCGGUGUU 1243 AACACCGGCAAGCAAUUUA siRNA 104 104 AAAUUGCUUGCCGGUGUUU 1244 AAACACCGGCAAGCAAUUU siRNA 105 105 AAUUGCUUGCCGGUGUUUU 1245 AAAACACCGGCAAGCAAUU siRNA 106 106 AUUGCUUGCCGGUGUUUUA 1246 UAAAACACCGGCAAGCAAU siRNA 107 107 UUGCUUGCCGGUGUUUUAA 1247 UUAAAACACCGGCAAGCAA siRNA 108 108 UGCUUGCCGGUGUUUUAAG 1248 CUUAAAACACCGGCAAGCA siRNA 109 109 GCUUGCCGGUGUUUUAAGA 1249 UCUUAAAACACCGGCAAGC siRNA 110 110 CUUGCCGGUGUUUUAAGAA 1250 UUCUUAAAACACCGGCAAG siRNA 111 111 UUGCCGGUGUUUUAAGAAA 1251 UUUCUUAAAACACCGGCAA siRNA 112 112 UGCCGGUGUUUUAAGAAAG 1252 CUUUCUUAAAACACCGGCA siRNA 113 113 GCCGGUGUUUUAAGAAAGC 1253 GCUUUCUUAAAACACCGGC siRNA 114 114 CCGGUGUUUUAAGAAAGCC 1254 GGCUUUCUUAAAACACCGG SIRNA 115 115 CGGUGUUUUAAGAAAGCCA 1255 UGGCUUUCUUAAAACACCG siRNA 116 116 GGUGUUUUAAGAAAGCCAG 1256 CUGGCUUUCUUAAAACACC siRNA 117 117 GUGUUUUAAGAAAGCCAGA 1257 UCUGGCUUUCUUAAAACAC SIRNA 118 118 UGUUUUAAGAAAGCCAGAU 1258 AUCUGGCUUUCUUAAAACA siRNA 119 119 GUUUUAAGAAAGCCAGAUG 1259 CAUCUGGCUUUCUUAAAAC siRNA 120 120 UUUUAAGAAAGCCAGAUGC 1260 GCAUCUGGCUUUCUUAAAA siRNA 121 121 UUUAAGAAAGCCAGAUGCC 1261 GGCAUCUGGCUUUCUUAAA siRNA 122 122 UUAAGAAAGCCAGAUGCCU 1262 AGGCAUCUGGCUUUCUUAA siRNA 123 123 UAAGAAAGCCAGAUGCCUG 1263 CAGGCAUCUGGCUUUCUUA siRNA 124 124 AAGAAAGCCAGAUGCCUGG 1264 CCAGGCAUCUGGCUUUCUU siRNA 125 125 AGAAAGCCAGAUGCCUGGA 1265 UCCAGGCAUCUGGCUUUCU siRNA 126 126 GAAAGCCAGAUGCCUGGAU 1266 AUCCAGGCAUCUGGCUUUC siRNA 127 127 AAAGCCAGAUGCCUGGAUU 1267 AAUCCAGGCAUCUGGCUUU siRNA 128 128 AAGCCAGAUGCCUGGAUUG 1268 CAAUCCAGGCAUCUGGCUU siRNA 129 129 AGCCAGAUGCCUGGAUUGG 1269 CCAAUCCAGGCAUCUGGCU siRNA 130 130 GCCAGAUGCCUGGAUUGGA 1270 UCCAAUCCAGGCAUCUGGC siRNA 131 131 CCAGAUGCCUGGAUUGGAC 1271 GUCCAAUCCAGGCAUCUGG siRNA 132 132 CAGAUGCCUGGAUUGGACU 1272 AGUCCAAUCCAGGCAUCUG SIRNA 133 133 AGAUGCCUGGAUUGGACUC 1273 GAGUCCAAUCCAGGCAUCU siRNA 134 134 GAUGCCUGGAUUGGACUCU 1274 AGAGUCCAAUCCAGGCAUC siRNA 135 135 AUGCCUGGAUUGGACUCUG 1275 CAGAGUCCAAUCCAGGCAU siRNA 136 136 UGCCUGGAUUGGACUCUGG 1276 CCAGAGUCCAAUCCAGGCA SiRNA 137 137 GCCUGGAUUGGACUCUGGG 1277 CCCAGAGUCCAAUCCAGGC siRNA 138 138 CCUGGAUUGGACUCUGGGG 1278 CCCCAGAGUCCAAUCCAGG siRNA 139 139 CUGGAUUGGACUCUGGGGU 1279 ACCCCAGAGUCCAAUCCAG siRNA 140 140 UGGAUUGGACUCUGGGGUG 1280 CACCCCAGAGUCCAAUCCA siRNA 141 141 GGAUUGGACUCUGGGGUGU 1281 ACACCCCAGAGUCCAAUCC siRNA 142 142 GAUUGGACUCUGGGGUGUU 1282 AACACCCCAGAGUCCAAUC siRNA 143 143 AUUGGACUCUGGGGUGUUC 1283 GAACACCCCAGAGUCCAAU siRNA 144 144 UUGGACUCUGGGGUGUUCU 1284 AGAACACCCCAGAGUCCAA siRNA 145 145 UGGACUCUGGGGUGUUCUC 1285 GAGAACACCCCAGAGUCCA siRNA 146 146 GGACUCUGGGGUGUUCUCC 1286 GGAGAACACCCCAGAGUCC siRNA 147 147 GACUCUGGGGUGUUCUCCG 1287 CGGAGAACACCCCAGAGUC siRNA 148 148 ACUCUGGGGUGUUCUCCGA 1288 UCGGAGAACACCCCAGAGU siRNA 149 149 CUCUGGGGUGUUCUCCGAG 1289 CUCGGAGAACACCCCAGAG siRNA 150 150 UCUGGGGUGUUCUCCGAGG 1290 CCUCGGAGAACACCCCAGA siRNA 151 151 CUGGGGUGUUCUCCGAGGG 1291 CCCUCGGAGAACACCCCAG siRNA 152 152 UGGGGUGUUCUCCGAGGGA 1292 UCCCUCGGAGAACACCCCA siRNA 153 153 GGGGUGUUCUCCGAGGGAC 1293 GUCCCUCGGAGAACACCCC siRNA 154 154 GGGUGUUCUCCGAGGGACA 1294 UGUCCCUCGGAGAACACCC siRNA 155 155 GGUGUUCUCCGAGGGACAC 1295 GUGUCCCUCGGAGAACACC siRNA 156 156 GUGUUCUCCGAGGGACACC 1296 GGUGUCCCUCGGAGAACAC siRNA 157 157 UGUUCUCCGAGGGACACCU 1297 AGGUGUCCCUCGGAGAACA siRNA 158 158 GUUCUCCGAGGGACACCUU 1298 AAGGUGUCCCUCGGAGAAC siRNA 159 159 UUCUCCGAGGGACACCUUC 1299 GAAGGUGUCCCUCGGAGAA siRNA 160 160 UCUCCGAGGGACACCUUCA 1300 UGAAGGUGUCCCUCGGAGA siRNA 161 161 CUCCGAGGGACACCUUCAU 1301 AUGAAGGUGUCCCUCGGAG siRNA 162 162 UCCGAGGGACACCUUCAUC 1302 GAUGAAGGUGUCCCUCGGA siRNA 163 163 CCGAGGGACACCUUCAUCA 1303 UGAUGAAGGUGUCCCUCGG siRNA 164 164 CGAGGGACACCUUCAUCAU 1304 AUGAUGAAGGUGUCCCUCG siRNA 165 165 GAGGGACACCUUCAUCAUA 1305 UAUGAUGAAGGUGUCCCUC siRNA 166 166 AGGGACACCUUCAUCAUAC 1306 GUAUGAUGAAGGUGUCCCU siRNA 167 167 GGGACACCUUCAUCAUACA 1307 UGUAUGAUGAAGGUGUCCC siRNA 168 168 GGACACCUUCAUCAUACAA 1308 UUGUAUGAUGAAGGUGUCC siRNA 169 169 GACACCUUCAUCAUACAAA 1309 UUUGUAUGAUGAAGGUGUC siRNA 170 170 ACACCUUCAUCAUACAAAC 1310 GUUUGUAUGAUGAAGGUGU siRNA 171 171 CACCUUCAUCAUACAAACU 1311 AGUUUGUAUGAUGAAGGUG siRNA 172 172 ACCUUCAUCAUACAAACUC 1312 GAGUUUGUAUGAUGAAGGU siRNA 173 173 CCUUCAUCAUACAAACUCU 1313 AGAGUUUGUAUGAUGAAGG siRNA 174 174 CUUCAUCAUACAAACUCUG 1314 CAGAGUUUGUAUGAUGAAG siRNA 175 175 UUCAUCAUACAAACUCUGU 1315 ACAGAGUUUGUAUGAUGAA siRNA 176 176 UCAUCAUACAAACUCUGUA 1316 UACAGAGUUUGUAUGAUGA siRNA 177 177 CAUCAUACAAACUCUGUAC 1317 GUACAGAGUUUGUAUGAUG siRNA 178 178 AUCAUACAAACUCUGUACU 1318 AGUACAGAGUUUGUAUGAU siRNA 179 179 UCAUACAAACUCUGUACUU 1319 AAGUACAGAGUUUGUAUGA siRNA 180 180 CAUACAAACUCUGUACUUC 1320 GAAGUACAGAGUUUGUAUG siRNA 181 181 AUACAAACUCUGUACUUCC 1321 GGAAGUACAGAGUUUGUAU siRNA 182 182 UACAAACUCUGUACUUCCU 1322 AGGAAGUACAGAGUUUGUA siRNA 183 183 ACAAACUCUGUACUUCCUG 1323 CAGGAAGUACAGAGUUUGU siRNA 184 184 CAAACUCUGUACUUCCUGG 1324 CCAGGAAGUACAGAGUUUG siRNA 185 185 AAACUCUGUACUUCCUGGA 1325 UCCAGGAAGUACAGAGUUU siRNA 186 186 AACUCUGUACUUCCUGGAA 1326 UUCCAGGAAGUACAGAGUU siRNA 187 187 ACUCUGUACUUCCUGGAAU 1327 AUUCCAGGAAGUACAGAGU siRNA 188 188 CUCUGUACUUCCUGGAAUC 1328 GAUUCCAGGAAGUACAGAG siRNA 189 189 UCUGUACUUCCUGGAAUCG 1329 CGAUUCCAGGAAGUACAGA siRNA 190 190 CUGUACUUCCUGGAAUCGA 1330 UCGAUUCCAGGAAGUACAG siRNA 191 191 UGUACUUCCUGGAAUCGAU 1331 AUCGAUUCCAGGAAGUACA siRNA 192 192 GUACUUCCUGGAAUCGAUA 1332 UAUCGAUUCCAGGAAGUAC siRNA 193 193 UACUUCCUGGAAUCGAUAC 1333 GUAUCGAUUCCAGGAAGUA siRNA 194 194 ACUUCCUGGAAUCGAUACU 1334 AGUAUCGAUUCCAGGAAGU siRNA 195 195 CUUCCUGGAAUCGAUACUU 1335 AAGUAUCGAUUCCAGGAAG siRNA 196 196 UUCCUGGAAUCGAUACUUG 1336 CAAGUAUCGAUUCCAGGAA siRNA 197 197 UCCUGGAAUCGAUACUUGU 1337 ACAAGUAUCGAUUCCAGGA siRNA 198 198 CCUGGAAUCGAUACUUGUA 1338 UACAAGUAUCGAUUCCAGG siRNA 199 199 CUGGAAUCGAUACUUGUAU 1339 AUACAAGUAUCGAUUCCAG siRNA 200 200 UGGAAUCGAUACUUGUAUU 1340 AAUACAAGUAUCGAUUCCA siRNA 201 201 GGAAUCGAUACUUGUAUUU 1341 AAAUACAAGUAUCGAUUCC siRNA 202 202 GAAUCGAUACUUGUAUUUU 1342 AAAAUACAAGUAUCGAUUC siRNA 203 203 AAUCGAUACUUGUAUUUUU 1343 AAAAAUACAAGUAUCGAUU siRNA 204 204 AUCGAUACUUGUAUUUUUC 1344 GAAAAAUACAAGUAUCGAU siRNA 205 205 UCGAUACUUGUAUUUUUCU 1345 AGAAAAAUACAAGUAUCGA siRNA 206 206 CGAUACUUGUAUUUUUCUA 1346 UAGAAAAAUACAAGUAUCG siRNA 207 207 GAUACUUGUAUUUUUCUAG 1347 CUAGAAAAAUACAAGUAUC siRNA 208 208 AUACUUGUAUUUUUCUAGU 1348 ACUAGAAAAAUACAAGUAU siRNA 209 209 UACUUGUAUUUUUCUAGUA 1349 UACUAGAAAAAUACAAGUA siRNA 210 210 ACUUGUAUUUUUCUAGUAC 1350 GUACUAGAAAAAUACAAGU siRNA 211 211 CUUGUAUUUUUCUAGUACC 1351 GGUACUAGAAAAAUACAAG siRNA 212 212 UUGUAUUUUUCUAGUACCA 1352 UGGUACUAGAAAAAUACAA siRNA 213 213 UGUAUUUUUCUAGUACCAA 1353 UUGGUACUAGAAAAAUACA siRNA 214 214 GUAUUUUUCUAGUACCAAG 1354 CUUGGUACUAGAAAAAUAC siRNA 215 215 UAUUUUUCUAGUACCAAGU 1355 ACUUGGUACUAGAAAAAUA siRNA 216 216 AUUUUUCUAGUACCAAGUU 1356 AACUUGGUACUAGAAAAAU siRNA 217 217 UUUUUCUAGUACCAAGUUA 1357 UAACUUGGUACUAGAAAAA siRNA 218 218 UUUUCUAGUACCAAGUUAC 1358 GUAACUUGGUACUAGAAAA siRNA 219 219 UUUCUAGUACCAAGUUACG 1359 CGUAACUUGGUACUAGAAA siRNA 220 220 UUCUAGUACCAAGUUACGU 1360 ACGUAACUUGGUACUAGAA siRNA 221 221 UCUAGUACCAAGUUACGUG 1361 CACGUAACUUGGUACUAGA siRNA 222 222 CUAGUACCAAGUUACGUGC 1362 GCACGUAACUUGGUACUAG siRNA 223 223 UAGUACCAAGUUACGUGCA 1363 UGCACGUAACUUGGUACUA siRNA 224 224 AGUACCAAGUUACGUGCAC 1364 GUGCACGUAACUUGGUACU siRNA 225 225 GUACCAAGUUACGUGCACC 1365 GGUGCACGUAACUUGGUAC siRNA 226 226 UACCAAGUUACGUGCACCA 1366 UGGUGCACGUAACUUGGUA siRNA 227 227 ACCAAGUUACGUGCACCAA 1367 UUGGUGCACGUAACUUGGU siRNA 228 228 CCAAGUUACGUGCACCAAA 1368 UUUGGUGCACGUAACUUGG siRNA 229 229 CAAGUUACGUGCACCAAAU 1369 AUUUGGUGCACGUAACUUG siRNA 230 230 AAGUUACGUGCACCAAAUU 1370 AAUUUGGUGCACGUAACUU siRNA 231 231 AGUUACGUGCACCAAAUUA 1371 UAAUUUGGUGCACGUAACU siRNA 232 232 GUUACGUGCACCAAAUUAU 1372 AUAAUUUGGUGCACGUAAC siRNA 233 233 UUACGUGCACCAAAUUAUA 1373 UAUAAUUUGGUGCACGUAA siRNA 234 234 UACGUGCACCAAAUUAUAA 1374 UUAUAAUUUGGUGCACGUA siRNA 235 235 ACGUGCACCAAAUUAUAAA 1375 UUUAUAAUUUGGUGCACGU siRNA 236 236 CGUGCACCAAAUUAUAAAA 1376 UUUUAUAAUUUGGUGCACG siRNA 237 237 GUGCACCAAAUUAUAAAAC 1377 GUUUUAUAAUUUGGUGCAC siRNA 238 238 UGCACCAAAUUAUAAAACA 1378 UGUUUUAUAAUUUGGUGCA siRNA 239 239 GCACCAAAUUAUAAAACAC 1379 GUGUUUUAUAAUUUGGUGC siRNA 240 240 CACCAAAUUAUAAAACACU 1380 AGUGUUUUAUAAUUUGGUG siRNA 241 241 ACCAAAUUAUAAAACACUU 1381 AAGUGUUUUAUAAUUUGGU siRNA 242 242 CCAAAUUAUAAAACACUUU 1382 AAAGUGUUUUAUAAUUUGG siRNA 243 243 CAAAUUAUAAAACACUUUU 1383 AAAAGUGUUUUAUAAUUUG siRNA 244 244 AAAUUAUAAAACACUUUUU 1384 AAAAAGUGUUUUAUAAUUU siRNA 245 245 AAUUAUAAAACACUUUUUU 1385 AAAAAAGUGUUUUAUAAUU siRNA 246 246 AUUAUAAAACACUUUUUUA 1386 UAAAAAAGUGUUUUAUAAU siRNA 247 247 UUAUAAAACACUUUUUUAU 1387 AUAAAAAAGUGUUUUAUAA siRNA 248 248 UAUAAAACACUUUUUUAUA 1388 UAUAAAAAAGUGUUUUAUA siRNA 249 249 AUAAAACACUUUUUUAUAA 1389 UUAUAAAAAAGUGUUUUAU siRNA 250 250 UAAAACACUUUUUUAUAAU 1390 AUUAUAAAAAAGUGUUUUA siRNA 251 251 AAAACACUUUUUUAUAAUA 1391 UAUUAUAAAAAAGUGUUUU siRNA 252 252 AAACACUUUUUUAUAAUAU 1392 AUAUUAUAAAAAAGUGUUU siRNA 253 253 AACACUUUUUUAUAAUAUU 1393 AAUAUUAUAAAAAAGUGUU siRNA 254 254 ACACUUUUUUAUAAUAUUU 1394 AAAUAUUAUAAAAAAGUGU siRNA 255 255 CACUUUUUUAUAAUAUUUU 1395 AAAAUAUUAUAAAAAAGUG siRNA 256 256 ACUUUUUUAUAAUAUUUUC 1396 GAAAAUAUUAUAAAAAAGU siRNA 257 257 CUUUUUUAUAAUAUUUUCU 1397 AGAAAAUAUUAUAAAAAAG siRNA 258 258 UUUUUUAUAAUAUUUUCUC 1398 GAGAAAAUAUUAUAAAAAA siRNA 259 259 UUUUUAUAAUAUUUUCUCA 1399 UGAGAAAAUAUUAUAAAAA siRNA 260 260 UUUUAUAAUAUUUUCUCAC 1400 GUGAGAAAAUAUUAUAAAA siRNA 261 261 UUUAUAAUAUUUUCUCACU 1401 AGUGAGAAAAUAUUAUAAA siRNA 262 262 UUAUAAUAUUUUCUCACUG 1402 CAGUGAGAAAAUAUUAUAA siRNA 263 263 UAUAAUAUUUUCUCACUGA 1403 UCAGUGAGAAAAUAUUAUA siRNA 264 264 AUAAUAUUUUCUCACUGAG 1404 CUCAGUGAGAAAAUAUUAU siRNA 265 265 UAAUAUUUUCUCACUGAGA 1405 UCUCAGUGAGAAAAUAUUA siRNA 266 266 AAUAUUUUCUCACUGAGAC 1406 GUCUCAGUGAGAAAAUAUU siRNA 267 267 AUAUUUUCUCACUGAGACU 1407 AGUCUCAGUGAGAAAAUAU siRNA 268 268 UAUUUUCUCACUGAGACUC 1408 GAGUCUCAGUGAGAAAAUA siRNA 269 269 AUUUUCUCACUGAGACUCC 1409 GGAGUCUCAGUGAGAAAAU siRNA 270 270 UUUUCUCACUGAGACUCCC 1410 GGGAGUCUCAGUGAGAAAA siRNA 271 271 UUUCUCACUGAGACUCCCA 1411 UGGGAGUCUCAGUGAGAAA siRNA 272 272 UUCUCACUGAGACUCCCAG 1412 CUGGGAGUCUCAGUGAGAA siRNA 273 273 UCUCACUGAGACUCCCAGG 1413 CCUGGGAGUCUCAGUGAGA siRNA 274 274 CUCACUGAGACUCCCAGGG 1414 CCCUGGGAGUCUCAGUGAG siRNA 275 275 UCACUGAGACUCCCAGGGC 1415 GCCCUGGGAGUCUCAGUGA siRNA 276 276 CACUGAGACUCCCAGGGCU 1416 AGCCCUGGGAGUCUCAGUG siRNA 277 277 ACUGAGACUCCCAGGGCUU 1417 AAGCCCUGGGAGUCUCAGU siRNA 278 278 CUGAGACUCCCAGGGCUUU 1418 AAAGCCCUGGGAGUCUCAG siRNA 279 279 UGAGACUCCCAGGGCUUUU 1419 AAAAGCCCUGGGAGUCUCA siRNA 280 280 GAGACUCCCAGGGCUUUUA 1420 UAAAAGCCCUGGGAGUCUC siRNA 281 281 AGACUCCCAGGGCUUUUAC 1421 GUAAAAGCCCUGGGAGUCU siRNA 282 282 GACUCCCAGGGCUUUUACU 1422 AGUAAAAGCCCUGGGAGUC siRNA 283 283 ACUCCCAGGGCUUUUACUA 1423 UAGUAAAAGCCCUGGGAGU siRNA 284 284 CUCCCAGGGCUUUUACUAU 1424 AUAGUAAAAGCCCUGGGAG siRNA 285 285 UCCCAGGGCUUUUACUAUC 1425 GAUAGUAAAAGCCCUGGGA siRNA 286 286 CCCAGGGCUUUUACUAUCU 1426 AGAUAGUAAAAGCCCUGGG siRNA 287 287 CCAGGGCUUUUACUAUCUC 1427 GAGAUAGUAAAAGCCCUGG siRNA 288 288 CAGGGCUUUUACUAUCUCC 1428 GGAGAUAGUAAAAGCCCUG siRNA 289 289 AGGGCUUUUACUAUCUCCA 1429 UGGAGAUAGUAAAAGCCCU siRNA 290 290 GGGCUUUUACUAUCUCCAG 1430 CUGGAGAUAGUAAAAGCCC siRNA 291 291 GGCUUUUACUAUCUCCAGA 1431 UCUGGAGAUAGUAAAAGCC siRNA 292 292 GCUUUUACUAUCUCCAGAA 1432 UUCUGGAGAUAGUAAAAGC siRNA 293 293 CUUUUACUAUCUCCAGAAU 1433 AUUCUGGAGAUAGUAAAAG siRNA 294 294 UUUUACUAUCUCCAGAAUG 1434 CAUUCUGGAGAUAGUAAAA siRNA 295 295 UUUACUAUCUCCAGAAUGU 1435 ACAUUCUGGAGAUAGUAAA siRNA 296 296 UUACUAUCUCCAGAAUGUA 1436 UACAUUCUGGAGAUAGUAA siRNA 297 297 UACUAUCUCCAGAAUGUAU 1437 AUACAUUCUGGAGAUAGUA siRNA 298 298 ACUAUCUCCAGAAUGUAUU 1438 AAUACAUUCUGGAGAUAGU siRNA 299 299 CUAUCUCCAGAAUGUAUUU 1439 AAAUACAUUCUGGAGAUAG siRNA 300 300 UAUCUCCAGAAUGUAUUUU 1440 AAAAUACAUUCUGGAGAUA siRNA 301 301 AUCUCCAGAAUGUAUUUUU 1441 AAAAAUACAUUCUGGAGAU siRNA 302 302 UCUCCAGAAUGUAUUUUUC 1442 GAAAAAUACAUUCUGGAGA siRNA 303 303 CUCCAGAAUGUAUUUUUCC 1443 GGAAAAAUACAUUCUGGAG siRNA 304 304 UCCAGAAUGUAUUUUUCCU 1444 AGGAAAAAUACAUUCUGGA siRNA 305 305 CCAGAAUGUAUUUUUCCUU 1445 AAGGAAAAAUACAUUCUGG siRNA 306 306 CAGAAUGUAUUUUUCCUUU 1446 AAAGGAAAAAUACAUUCUG siRNA 307 307 AGAAUGUAUUUUUCCUUUU 1447 AAAAGGAAAAAUACAUUCU siRNA 308 308 GAAUGUAUUUUUCCUUUUU 1448 AAAAAGGAAAAAUACAUUC siRNA 309 309 AAUGUAUUUUUCCUUUUUC 1449 GAAAAAGGAAAAAUACAUU siRNA 310 310 AUGUAUUUUUCCUUUUUCC 1450 GGAAAAAGGAAAAAUACAU siRNA 311 311 UGUAUUUUUCCUUUUUCCG 1451 CGGAAAAAGGAAAAAUACA siRNA 312 312 GUAUUUUUCCUUUUUCCGU 1452 ACGGAAAAAGGAAAAAUAC siRNA 313 313 UAUUUUUCCUUUUUCCGUA 1453 UACGGAAAAAGGAAAAAUA siRNA 314 314 AUUUUUCCUUUUUCCGUAA 1454 UUACGGAAAAAGGAAAAAU siRNA 315 315 UUUUUCCUUUUUCCGUAAG 1455 CUUACGGAAAAAGGAAAAA siRNA 316 316 UUUUCCUUUUUCCGUAAGA 1456 UCUUACGGAAAAAGGAAAA siRNA 317 317 UUUCCUUUUUCCGUAAGAC 1457 GUCUUACGGAAAAAGGAAA siRNA 318 318 UUCCUUUUUCCGUAAGACU 1458 AGUCUUACGGAAAAAGGAA siRNA 319 319 UCCUUUUUCCGUAAGACUC 1459 GAGUCUUACGGAAAAAGGA siRNA 320 320 CCUUUUUCCGUAAGACUCA 1460 UGAGUCUUACGGAAAAAGG siRNA 321 321 CUUUUUCCGUAAGACUCAA 1461 UUGAGUCUUACGGAAAAAG siRNA 322 322 UUUUUCCGUAAGACUCAAA 1462 UUUGAGUCUUACGGAAAAA siRNA 323 323 UUUUCCGUAAGACUCAAAA 1463 UUUUGAGUCUUACGGAAAA siRNA 324 324 UUUCCGUAAGACUCAAAAG 1464 CUUUUGAGUCUUACGGAAA siRNA 325 325 UUCCGUAAGACUCAAAAGU 1465 ACUUUUGAGUCUUACGGAA siRNA 326 326 UCCGUAAGACUCAAAAGUA 1466 UACUUUUGAGUCUUACGGA siRNA 327 327 CCGUAAGACUCAAAAGUAA 1467 UUACUUUUGAGUCUUACGG siRNA 328 328 CGUAAGACUCAAAAGUAAU 1468 AUUACUUUUGAGUCUUACG siRNA 329 329 GUAAGACUCAAAAGUAAUA 1469 UAUUACUUUUGAGUCUUAC siRNA 330 330 UAAGACUCAAAAGUAAUAU 1470 AUAUUACUUUUGAGUCUUA siRNA 331 331 AAGACUCAAAAGUAAUAUA 1471 UAUAUUACUUUUGAGUCUU siRNA 332 332 AGACUCAAAAGUAAUAUAA 1472 UUAUAUUACUUUUGAGUCU siRNA 333 333 GACUCAAAAGUAAUAUAAG 1473 CUUAUAUUACUUUUGAGUC siRNA 334 334 ACUCAAAAGUAAUAUAAGG 1474 CCUUAUAUUACUUUUGAGU siRNA 335 335 CUCAAAAGUAAUAUAAGGU 1475 ACCUUAUAUUACUUUUGAG siRNA 336 336 UCAAAAGUAAUAUAAGGUC 1476 GACCUUAUAUUACUUUUGA siRNA 337 337 CAAAAGUAAUAUAAGGUCU 1477 AGACCUUAUAUUACUUUUG siRNA 338 338 AAAAGUAAUAUAAGGUCUA 1478 UAGACCUUAUAUUACUUUU siRNA 339 339 AAAGUAAUAUAAGGUCUAC 1479 GUAGACCUUAUAUUACUUU siRNA 340 340 AAGUAAUAUAAGGUCUACA 1480 UGUAGACCUUAUAUUACUU siRNA 341 341 AGUAAUAUAAGGUCUACAA 1481 UUGUAGACCUUAUAUUACU siRNA 342 342 GUAAUAUAAGGUCUACAAA 1482 UUUGUAGACCUUAUAUUAC siRNA 343 343 UAAUAUAAGGUCUACAAAA 1483 UUUUGUAGACCUUAUAUUA siRNA 344 344 AAUAUAAGGUCUACAAAAU 1484 AUUUUGUAGACCUUAUAUU siRNA 345 345 AUAUAAGGUCUACAAAAUC 1485 GAUUUUGUAGACCUUAUAU siRNA 346 346 UAUAAGGUCUACAAAAUCU 1486 AGAUUUUGUAGACCUUAUA siRNA 347 347 AUAAGGUCUACAAAAUCUA 1487 UAGAUUUUGUAGACCUUAU siRNA 348 348 UAAGGUCUACAAAAUCUAC 1488 GUAGAUUUUGUAGACCUUA siRNA 349 349 AAGGUCUACAAAAUCUACU 1489 AGUAGAUUUUGUAGACCUU siRNA 350 350 AGGUCUACAAAAUCUACUA 1490 UAGUAGAUUUUGUAGACCU siRNA 351 351 GGUCUACAAAAUCUACUAA 1491 UUAGUAGAUUUUGUAGACC siRNA 352 352 GUCUACAAAAUCUACUAAA 1492 UUUAGUAGAUUUUGUAGAC siRNA 353 353 UCUACAAAAUCUACUAAAA 1493 UUUUAGUAGAUUUUGUAGA siRNA 354 354 CUACAAAAUCUACUAAAAA 1494 UUUUUAGUAGAUUUUGUAG siRNA 355 355 UACAAAAUCUACUAAAAAG 1495 CUUUUUAGUAGAUUUUGUA siRNA 356 356 ACAAAAUCUACUAAAAAGU 1496 ACUUUUUAGUAGAUUUUGU siRNA 357 357 CAAAAUCUACUAAAAAGUC 1497 GACUUUUUAGUAGAUUUUG siRNA 358 358 AAAAUCUACUAAAAAGUCU 1498 AGACUUUUUAGUAGAUUUU siRNA 359 359 AAAUCUACUAAAAAGUCUC 1499 GAGACUUUUUAGUAGAUUU siRNA 360 360 AAUCUACUAAAAAGUCUCU 1500 AGAGACUUUUUAGUAGAUU siRNA 361 361 AUCUACUAAAAAGUCUCUG 1501 CAGAGACUUUUUAGUAGAU siRNA 362 362 UCUACUAAAAAGUCUCUGC 1502 GCAGAGACUUUUUAGUAGA siRNA 363 363 CUACUAAAAAGUCUCUGCA 1503 UGCAGAGACUUUUUAGUAG siRNA 364 364 UACUAAAAAGUCUCUGCAA 1504 UUGCAGAGACUUUUUAGUA siRNA 365 365 ACUAAAAAGUCUCUGCAAA 1505 UUUGCAGAGACUUUUUAGU siRNA 366 366 CUAAAAAGUCUCUGCAAAA 1506 UUUUGCAGAGACUUUUUAG siRNA 367 367 UAAAAAGUCUCUGCAAAAA 1507 UUUUUGCAGAGACUUUUUA siRNA 368 368 AAAAAGUCUCUGCAAAAAG 1508 CUUUUUGCAGAGACUUUUU siRNA 369 369 AAAAGUCUCUGCAAAAAGU 1509 ACUUUUUGCAGAGACUUUU siRNA 370 370 AAAGUCUCUGCAAAAAGUA 1510 UACUUUUUGCAGAGACUUU siRNA 371 371 AAGUCUCUGCAAAAAGUAG 1511 CUACUUUUUGCAGAGACUU siRNA 372 372 AGUCUCUGCAAAAAGUAGA 1512 UCUACUUUUUGCAGAGACU siRNA 373 373 GUCUCUGCAAAAAGUAGAU 1513 AUCUACUUUUUGCAGAGAC siRNA 374 374 UCUCUGCAAAAAGUAGAUG 1514 CAUCUACUUUUUGCAGAGA siRNA 375 375 CUCUGCAAAAAGUAGAUGA 1515 UCAUCUACUUUUUGCAGAG siRNA 376 376 UCUGCAAAAAGUAGAUGAA 1516 UUCAUCUACUUUUUGCAGA siRNA 377 377 CUGCAAAAAGUAGAUGAAG 1517 CUUCAUCUACUUUUUGCAG siRNA 378 378 UGCAAAAAGUAGAUGAAGA 1518 UCUUCAUCUACUUUUUGCA siRNA 379 379 GCAAAAAGUAGAUGAAGAG 1519 CUCUUCAUCUACUUUUUGC siRNA 380 380 CAAAAAGUAGAUGAAGAGG 1520 CCUCUUCAUCUACUUUUUG siRNA 381 381 AAAAAGUAGAUGAAGAGGA 1521 UCCUCUUCAUCUACUUUUU siRNA 382 382 AAAAGUAGAUGAAGAGGAC 1522 GUCCUCUUCAUCUACUUUU SIRNA 383 383 AAAGUAGAUGAAGAGGACU 1523 AGUCCUCUUCAUCUACUUU siRNA 384 384 AAGUAGAUGAAGAGGACUC 1524 GAGUCCUCUUCAUCUACUU siRNA 385 385 AGUAGAUGAAGAGGACUCU 1525 AGAGUCCUCUUCAUCUACU siRNA 386 386 GUAGAUGAAGAGGACUCUG 1526 CAGAGUCCUCUUCAUCUAC siRNA 387 387 UAGAUGAAGAGGACUCUGA 1527 UCAGAGUCCUCUUCAUCUA siRNA 388 388 AGAUGAAGAGGACUCUGAU 1528 AUCAGAGUCCUCUUCAUCU siRNA 389 389 GAUGAAGAGGACUCUGAUG 1529 CAUCAGAGUCCUCUUCAUC siRNA 390 390 AUGAAGAGGACUCUGAUGA 1530 UCAUCAGAGUCCUCUUCAU siRNA 391 391 UGAAGAGGACUCUGAUGAA 1531 UUCAUCAGAGUCCUCUUCA siRNA 392 392 GAAGAGGACUCUGAUGAAG 1532 CUUCAUCAGAGUCCUCUUC siRNA 393 393 AAGAGGACUCUGAUGAAGA 1533 UCUUCAUCAGAGUCCUCUU siRNA 394 394 AGAGGACUCUGAUGAAGAA 1534 UUCUUCAUCAGAGUCCUCU siRNA 395 395 GAGGACUCUGAUGAAGAAA 1535 UUUCUUCAUCAGAGUCCUC siRNA 396 396 AGGACUCUGAUGAAGAAAG 1536 CUUUCUUCAUCAGAGUCCU siRNA 397 397 GGACUCUGAUGAAGAAAGC 1537 GCUUUCUUCAUCAGAGUCC siRNA 398 398 GACUCUGAUGAAGAAAGCC 1538 GGCUUUCUUCAUCAGAGUC siRNA 399 399 ACUCUGAUGAAGAAAGCCA 1539 UGGCUUUCUUCAUCAGAGU siRNA 400 400 CUCUGAUGAAGAAAGCCAU 1540 AUGGCUUUCUUCAUCAGAG siRNA 401 401 UCUGAUGAAGAAAGCCAUC 1541 GAUGGCUUUCUUCAUCAGA siRNA 402 402 CUGAUGAAGAAAGCCAUCA 1542 UGAUGGCUUUCUUCAUCAG siRNA 403 403 UGAUGAAGAAAGCCAUCAU 1543 AUGAUGGCUUUCUUCAUCA siRNA 404 404 GAUGAAGAAAGCCAUCAUG 1544 CAUGAUGGCUUUCUUCAUC siRNA 405 405 AUGAAGAAAGCCAUCAUGA 1545 UCAUGAUGGCUUUCUUCAU siRNA 406 406 UGAAGAAAGCCAUCAUGAU 1546 AUCAUGAUGGCUUUCUUCA siRNA 407 407 GAAGAAAGCCAUCAUGAUG 1547 CAUCAUGAUGGCUUUCUUC siRNA 408 408 AAGAAAGCCAUCAUGAUGA 1548 UCAUCAUGAUGGCUUUCUU siRNA 409 409 AGAAAGCCAUCAUGAUGAG 1549 CUCAUCAUGAUGGCUUUCU siRNA 410 410 GAAAGCCAUCAUGAUGAGA 1550 UCUCAUCAUGAUGGCUUUC siRNA 411 411 AAAGCCAUCAUGAUGAGAU 1551 AUCUCAUCAUGAUGGCUUU siRNA 412 412 AAGCCAUCAUGAUGAGAUG 1552 CAUCUCAUCAUGAUGGCUU siRNA 413 413 AGCCAUCAUGAUGAGAUGA 1553 UCAUCUCAUCAUGAUGGCU siRNA 414 414 GCCAUCAUGAUGAGAUGAG 1554 CUCAUCUCAUCAUGAUGGC siRNA 415 415 CCAUCAUGAUGAGAUGAGU 1555 ACUCAUCUCAUCAUGAUGG SIRNA 416 416 CAUCAUGAUGAGAUGAGUG 1556 CACUCAUCUCAUCAUGAUG siRNA 417 417 AUCAUGAUGAGAUGAGUGA 1557 UCACUCAUCUCAUCAUGAU siRNA 418 418 UCAUGAUGAGAUGAGUGAG 1558 CUCACUCAUCUCAUCAUGA siRNA 419 419 CAUGAUGAGAUGAGUGAGC 1559 GCUCACUCAUCUCAUCAUG siRNA 420 420 AUGAUGAGAUGAGUGAGCA 1560 UGCUCACUCAUCUCAUCAU siRNA 421 421 UGAUGAGAUGAGUGAGCAG 1561 CUGCUCACUCAUCUCAUCA siRNA 422 422 GAUGAGAUGAGUGAGCAGG 1562 CCUGCUCACUCAUCUCAUC siRNA 423 423 AUGAGAUGAGUGAGCAGGA 1563 UCCUGCUCACUCAUCUCAU siRNA 424 424 UGAGAUGAGUGAGCAGGAA 1564 UUCCUGCUCACUCAUCUCA siRNA 425 425 GAGAUGAGUGAGCAGGAAG 1565 CUUCCUGCUCACUCAUCUC siRNA 426 426 AGAUGAGUGAGCAGGAAGA 1566 UCUUCCUGCUCACUCAUCU siRNA 427 427 GAUGAGUGAGCAGGAAGAG 1567 CUCUUCCUGCUCACUCAUC siRNA 428 428 AUGAGUGAGCAGGAAGAGG 1568 CCUCUUCCUGCUCACUCAU siRNA 429 429 UGAGUGAGCAGGAAGAGGA 1569 UCCUCUUCCUGCUCACUCA siRNA 430 430 GAGUGAGCAGGAAGAGGAG 1570 CUCCUCUUCCUGCUCACUC siRNA 431 431 AGUGAGCAGGAAGAGGAGC 1571 GCUCCUCUUCCUGCUCACU siRNA 432 432 GUGAGCAGGAAGAGGAGCU 1572 AGCUCCUCUUCCUGCUCAC siRNA 433 433 UGAGCAGGAAGAGGAGCUU 1573 AAGCUCCUCUUCCUGCUCA siRNA 434 434 GAGCAGGAAGAGGAGCUUG 1574 CAAGCUCCUCUUCCUGCUC siRNA 435 435 AGCAGGAAGAGGAGCUUGA 1575 UCAAGCUCCUCUUCCUGCU siRNA 436 436 GCAGGAAGAGGAGCUUGAG 1576 CUCAAGCUCCUCUUCCUGC siRNA 437 437 CAGGAAGAGGAGCUUGAGG 1577 CCUCAAGCUCCUCUUCCUG siRNA 438 438 AGGAAGAGGAGCUUGAGGA 1578 UCCUCAAGCUCCUCUUCCU siRNA 439 439 GGAAGAGGAGCUUGAGGAU 1579 AUCCUCAAGCUCCUCUUCC siRNA 440 440 GAAGAGGAGCUUGAGGAUG 1580 CAUCCUCAAGCUCCUCUUC siRNA 441 441 AAGAGGAGCUUGAGGAUGA 1581 UCAUCCUCAAGCUCCUCUU siRNA 442 442 AGAGGAGCUUGAGGAUGAU 1582 AUCAUCCUCAAGCUCCUCU siRNA 443 443 GAGGAGCUUGAGGAUGAUC 1583 GAUCAUCCUCAAGCUCCUC siRNA 444 444 AGGAGCUUGAGGAUGAUCC 1584 GGAUCAUCCUCAAGCUCCU siRNA 445 445 GGAGCUUGAGGAUGAUCCU 1585 AGGAUCAUCCUCAAGCUCC siRNA 446 446 GAGCUUGAGGAUGAUCCUA 1586 UAGGAUCAUCCUCAAGCUC siRNA 447 447 AGCUUGAGGAUGAUCCUAC 1587 GUAGGAUCAUCCUCAAGCU siRNA 448 448 GCUUGAGGAUGAUCCUACU 1588 AGUAGGAUCAUCCUCAAGC siRNA 449 449 CUUGAGGAUGAUCCUACUG 1589 CAGUAGGAUCAUCCUCAAG siRNA 450 450 UUGAGGAUGAUCCUACUGU 1590 ACAGUAGGAUCAUCCUCAA siRNA 451 451 UGAGGAUGAUCCUACUGUA 1591 UACAGUAGGAUCAUCCUCA siRNA 452 452 GAGGAUGAUCCUACUGUAG 1592 CUACAGUAGGAUCAUCCUC siRNA 453 453 AGGAUGAUCCUACUGUAGU 1593 ACUACAGUAGGAUCAUCCU siRNA 454 454 GGAUGAUCCUACUGUAGUC 1594 GACUACAGUAGGAUCAUCC siRNA 455 455 GAUGAUCCUACUGUAGUCA 1595 UGACUACAGUAGGAUCAUC siRNA 456 456 AUGAUCCUACUGUAGUCAA 1596 UUGACUACAGUAGGAUCAU siRNA 457 457 UGAUCCUACUGUAGUCAAA 1597 UUUGACUACAGUAGGAUCA siRNA 458 458 GAUCCUACUGUAGUCAAAA 1598 UUUUGACUACAGUAGGAUC siRNA 459 459 AUCCUACUGUAGUCAAAAA 1599 UUUUUGACUACAGUAGGAU siRNA 460 460 UCCUACUGUAGUCAAAAAC 1600 GUUUUUGACUACAGUAGGA siRNA 461 461 CCUACUGUAGUCAAAAACU 1601 AGUUUUUGACUACAGUAGG siRNA 462 462 CUACUGUAGUCAAAAACUA 1602 UAGUUUUUGACUACAGUAG siRNA 463 463 UACUGUAGUCAAAAACUAU 1603 AUAGUUUUUGACUACAGUA siRNA 464 464 ACUGUAGUCAAAAACUAUA 1604 UAUAGUUUUUGACUACAGU siRNA 465 465 CUGUAGUCAAAAACUAUAA 1605 UUAUAGUUUUUGACUACAG siRNA 466 466 UGUAGUCAAAAACUAUAAA 1606 UUUAUAGUUUUUGACUACA siRNA 467 467 GUAGUCAAAAACUAUAAAG 1607 CUUUAUAGUUUUUGACUAC siRNA 468 468 UAGUCAAAAACUAUAAAGA 1608 UCUUUAUAGUUUUUGACUA siRNA 469 469 AGUCAAAAACUAUAAAGAC 1609 GUCUUUAUAGUUUUUGACU siRNA 470 470 GUCAAAAACUAUAAAGACC 1610 GGUCUUUAUAGUUUUUGAC siRNA 471 471 UCAAAAACUAUAAAGACCU 1611 AGGUCUUUAUAGUUUUUGA siRNA 472 472 CAAAAACUAUAAAGACCUG 1612 CAGGUCUUUAUAGUUUUUG siRNA 473 473 AAAAACUAUAAAGACCUGG 1613 CCAGGUCUUUAUAGUUUUU siRNA 474 474 AAAACUAUAAAGACCUGGA 1614 UCCAGGUCUUUAUAGUUUU siRNA 475 475 AAACUAUAAAGACCUGGAA 1615 UUCCAGGUCUUUAUAGUUU siRNA 476 476 AACUAUAAAGACCUGGAAA 1616 UUUCCAGGUCUUUAUAGUU siRNA 477 477 ACUAUAAAGACCUGGAAAA 1617 UUUUCCAGGUCUUUAUAGU siRNA 478 478 CUAUAAAGACCUGGAAAAA 1618 UUUUUCCAGGUCUUUAUAG siRNA 479 479 UAUAAAGACCUGGAAAAAG 1619 CUUUUUCCAGGUCUUUAUA siRNA 480 480 AUAAAGACCUGGAAAAAGC 1620 GCUUUUUCCAGGUCUUUAU siRNA 481 481 UAAAGACCUGGAAAAAGCA 1621 UGCUUUUUCCAGGUCUUUA siRNA 482 482 AAAGACCUGGAAAAAGCAG 1622 CUGCUUUUUCCAGGUCUUU siRNA 483 483 AAGACCUGGAAAAAGCAGU 1623 ACUGCUUUUUCCAGGUCUU siRNA 484 484 AGACCUGGAAAAAGCAGUU 1624 AACUGCUUUUUCCAGGUCU siRNA 485 485 GACCUGGAAAAAGCAGUUC 1625 GAACUGCUUUUUCCAGGUC siRNA 486 486 ACCUGGAAAAAGCAGUUCA 1626 UGAACUGCUUUUUCCAGGU siRNA 487 487 CCUGGAAAAAGCAGUUCAG 1627 CUGAACUGCUUUUUCCAGG siRNA 488 488 CUGGAAAAAGCAGUUCAGU 1628 ACUGAACUGCUUUUUCCAG siRNA 489 489 UGGAAAAAGCAGUUCAGUC 1629 GACUGAACUGCUUUUUCCA siRNA 490 490 GGAAAAAGCAGUUCAGUCU 1630 AGACUGAACUGCUUUUUCC siRNA 491 491 GAAAAAGCAGUUCAGUCUU 1631 AAGACUGAACUGCUUUUUC siRNA 492 492 AAAAAGCAGUUCAGUCUUU 1632 AAAGACUGAACUGCUUUUU siRNA 493 493 AAAAGCAGUUCAGUCUUUU 1633 AAAAGACUGAACUGCUUUU siRNA 494 494 AAAGCAGUUCAGUCUUUUC 1634 GAAAAGACUGAACUGCUUU siRNA 495 495 AAGCAGUUCAGUCUUUUCG 1635 CGAAAAGACUGAACUGCUU siRNA 496 496 AGCAGUUCAGUCUUUUCGG 1636 CCGAAAAGACUGAACUGCU siRNA 497 497 GCAGUUCAGUCUUUUCGGU 1637 ACCGAAAAGACUGAACUGC siRNA 498 498 CAGUUCAGUCUUUUCGGUA 1638 UACCGAAAAGACUGAACUG siRNA 499 499 AGUUCAGUCUUUUCGGUAU 1639 AUACCGAAAAGACUGAACU siRNA 500 500 GUUCAGUCUUUUCGGUAUG 1640 CAUACCGAAAAGACUGAAC siRNA 501 501 UUCAGUCUUUUCGGUAUGA 1641 UCAUACCGAAAAGACUGAA siRNA 502 502 UCAGUCUUUUCGGUAUGAU 1642 AUCAUACCGAAAAGACUGA siRNA 503 503 CAGUCUUUUCGGUAUGAUG 1643 CAUCAUACCGAAAAGACUG siRNA 504 504 AGUCUUUUCGGUAUGAUGU 1644 ACAUCAUACCGAAAAGACU siRNA 505 505 GUCUUUUCGGUAUGAUGUU 1645 AACAUCAUACCGAAAAGAC siRNA 506 506 UCUUUUCGGUAUGAUGUUG 1646 CAACAUCAUACCGAAAAGA siRNA 507 507 CUUUUCGGUAUGAUGUUGU 1647 ACAACAUCAUACCGAAAAG siRNA 508 508 UUUUCGGUAUGAUGUUGUC 1648 GACAACAUCAUACCGAAAA siRNA 509 509 UUUCGGUAUGAUGUUGUCC 1649 GGACAACAUCAUACCGAAA siRNA 510 510 UUCGGUAUGAUGUUGUCCU 1650 AGGACAACAUCAUACCGAA siRNA 511 511 UCGGUAUGAUGUUGUCCUG 1651 CAGGACAACAUCAUACCGA siRNA 512 512 CGGUAUGAUGUUGUCCUGA 1652 UCAGGACAACAUCAUACCG siRNA 513 513 GGUAUGAUGUUGUCCUGAA 1653 UUCAGGACAACAUCAUACC siRNA 514 514 GUAUGAUGUUGUCCUGAAG 1654 CUUCAGGACAACAUCAUAC siRNA 515 515 UAUGAUGUUGUCCUGAAGA 1655 UCUUCAGGACAACAUCAUA siRNA 516 516 AUGAUGUUGUCCUGAAGAC 1656 GUCUUCAGGACAACAUCAU siRNA 517 517 UGAUGUUGUCCUGAAGACG 1657 CGUCUUCAGGACAACAUCA siRNA 518 518 GAUGUUGUCCUGAAGACGG 1658 CCGUCUUCAGGACAACAUC siRNA 519 519 AUGUUGUCCUGAAGACGGG 1659 CCCGUCUUCAGGACAACAU siRNA 520 520 UGUUGUCCUGAAGACGGGG 1660 CCCCGUCUUCAGGACAACA siRNA 521 521 GUUGUCCUGAAGACGGGGC 1661 GCCCCGUCUUCAGGACAAC siRNA 522 522 UUGUCCUGAAGACGGGGCU 1662 AGCCCCGUCUUCAGGACAA siRNA 523 523 UGUCCUGAAGACGGGGCUA 1663 UAGCCCCGUCUUCAGGACA siRNA 524 524 GUCCUGAAGACGGGGCUAG 1664 CUAGCCCCGUCUUCAGGAC siRNA 525 525 UCCUGAAGACGGGGCUAGA 1665 UCUAGCCCCGUCUUCAGGA siRNA 526 526 CCUGAAGACGGGGCUAGAU 1666 AUCUAGCCCCGUCUUCAGG siRNA 527 527 CUGAAGACGGGGCUAGAUA 1667 UAUCUAGCCCCGUCUUCAG siRNA 528 528 UGAAGACGGGGCUAGAUAU 1668 AUAUCUAGCCCCGUCUUCA siRNA 529 529 GAAGACGGGGCUAGAUAUU 1669 AAUAUCUAGCCCCGUCUUC siRNA 530 530 AAGACGGGGCUAGAUAUUG 1670 CAAUAUCUAGCCCCGUCUU siRNA 531 531 AGACGGGGCUAGAUAUUGG 1671 CCAAUAUCUAGCCCCGUCU siRNA 532 532 GACGGGGCUAGAUAUUGGG 1672 CCCAAUAUCUAGCCCCGUC siRNA 533 533 ACGGGGCUAGAUAUUGGGA 1673 UCCCAAUAUCUAGCCCCGU siRNA 534 534 CGGGGCUAGAUAUUGGGAG 1674 CUCCCAAUAUCUAGCCCCG siRNA 535 535 GGGGCUAGAUAUUGGGAGA 1675 UCUCCCAAUAUCUAGCCCC siRNA 536 536 GGGCUAGAUAUUGGGAGAA 1676 UUCUCCCAAUAUCUAGCCC siRNA 537 537 GGCUAGAUAUUGGGAGAAA 1677 UUUCUCCCAAUAUCUAGCC siRNA 538 538 GCUAGAUAUUGGGAGAAAC 1678 GUUUCUCCCAAUAUCUAGC siRNA 539 539 CUAGAUAUUGGGAGAAACA 1679 UGUUUCUCCCAAUAUCUAG siRNA 540 540 UAGAUAUUGGGAGAAACAA 1680 UUGUUUCUCCCAAUAUCUA siRNA 541 541 AGAUAUUGGGAGAAACAAA 1681 UUUGUUUCUCCCAAUAUCU siRNA 542 542 GAUAUUGGGAGAAACAAAG 1682 CUUUGUUUCUCCCAAUAUC siRNA 543 543 AUAUUGGGAGAAACAAAGU 1683 ACUUUGUUUCUCCCAAUAU siRNA 544 544 UAUUGGGAGAAACAAAGUG 1684 CACUUUGUUUCUCCCAAUA siRNA 545 545 AUUGGGAGAAACAAAGUGG 1685 CCACUUUGUUUCUCCCAAU siRNA 546 546 UUGGGAGAAACAAAGUGGA 1686 UCCACUUUGUUUCUCCCAA siRNA 547 547 UGGGAGAAACAAAGUGGAA 1687 UUCCACUUUGUUUCUCCCA siRNA 548 548 GGGAGAAACAAAGUGGAAG 1688 CUUCCACUUUGUUUCUCCC siRNA 549 549 GGAGAAACAAAGUGGAAGA 1689 UCUUCCACUUUGUUUCUCC siRNA 550 550 GAGAAACAAAGUGGAAGAU 1690 AUCUUCCACUUUGUUUCUC siRNA 551 551 AGAAACAAAGUGGAAGAUG 1691 CAUCUUCCACUUUGUUUCU siRNA 552 552 GAAACAAAGUGGAAGAUGC 1692 GCAUCUUCCACUUUGUUUC siRNA 553 553 AAACAAAGUGGAAGAUGCU 1693 AGCAUCUUCCACUUUGUUU siRNA 554 554 AACAAAGUGGAAGAUGCUU 1694 AAGCAUCUUCCACUUUGUU siRNA 555 555 ACAAAGUGGAAGAUGCUUU 1695 AAAGCAUCUUCCACUUUGU siRNA 556 556 CAAAGUGGAAGAUGCUUUC 1696 GAAAGCAUCUUCCACUUUG siRNA 557 557 AAAGUGGAAGAUGCUUUCU 1697 AGAAAGCAUCUUCCACUUU siRNA 558 558 AAGUGGAAGAUGCUUUCUA 1698 UAGAAAGCAUCUUCCACUU siRNA 559 559 AGUGGAAGAUGCUUUCUAC 1699 GUAGAAAGCAUCUUCCACU siRNA 560 560 GUGGAAGAUGCUUUCUACA 1700 UGUAGAAAGCAUCUUCCAC siRNA 561 561 UGGAAGAUGCUUUCUACAA 1701 UUGUAGAAAGCAUCUUCCA siRNA 562 562 GGAAGAUGCUUUCUACAAA 1702 UUUGUAGAAAGCAUCUUCC siRNA 563 563 GAAGAUGCUUUCUACAAAG 1703 CUUUGUAGAAAGCAUCUUC siRNA 564 564 AAGAUGCUUUCUACAAAGG 1704 CCUUUGUAGAAAGCAUCUU siRNA 565 565 AGAUGCUUUCUACAAAGGU 1705 ACCUUUGUAGAAAGCAUCU siRNA 566 566 GAUGCUUUCUACAAAGGUG 1706 CACCUUUGUAGAAAGCAUC siRNA 567 567 AUGCUUUCUACAAAGGUGA 1707 UCACCUUUGUAGAAAGCAU siRNA 568 568 UGCUUUCUACAAAGGUGAA 1708 UUCACCUUUGUAGAAAGCA siRNA 569 569 GCUUUCUACAAAGGUGAAC 1709 GUUCACCUUUGUAGAAAGC siRNA 570 570 CUUUCUACAAAGGUGAACU 1710 AGUUCACCUUUGUAGAAAG siRNA 571 571 UUUCUACAAAGGUGAACUC 1711 GAGUUCACCUUUGUAGAAA siRNA 572 572 UUCUACAAAGGUGAACUCA 1712 UGAGUUCACCUUUGUAGAA siRNA 573 573 UCUACAAAGGUGAACUCAG 1713 CUGAGUUCACCUUUGUAGA siRNA 574 574 CUACAAAGGUGAACUCAGG 1714 CCUGAGUUCACCUUUGUAG siRNA 575 575 UACAAAGGUGAACUCAGGC 1715 GCCUGAGUUCACCUUUGUA siRNA 576 576 ACAAAGGUGAACUCAGGCU 1716 AGCCUGAGUUCACCUUUGU siRNA 577 577 CAAAGGUGAACUCAGGCUG 1717 CAGCCUGAGUUCACCUUUG siRNA 578 578 AAAGGUGAACUCAGGCUGA 1718 UCAGCCUGAGUUCACCUUU siRNA 579 579 AAGGUGAACUCAGGCUGAA 1719 UUCAGCCUGAGUUCACCUU siRNA 580 580 AGGUGAACUCAGGCUGAAU 1720 AUUCAGCCUGAGUUCACCU siRNA 581 581 GGUGAACUCAGGCUGAAUG 1721 CAUUCAGCCUGAGUUCACC siRNA 582 582 GUGAACUCAGGCUGAAUGA 1722 UCAUUCAGCCUGAGUUCAC siRNA 583 583 UGAACUCAGGCUGAAUGAG 1723 CUCAUUCAGCCUGAGUUCA siRNA 584 584 GAACUCAGGCUGAAUGAGG 1724 CCUCAUUCAGCCUGAGUUC siRNA 585 585 AACUCAGGCUGAAUGAGGA 1725 UCCUCAUUCAGCCUGAGUU siRNA 586 586 ACUCAGGCUGAAUGAGGAA 1726 UUCCUCAUUCAGCCUGAGU siRNA 587 587 CUCAGGCUGAAUGAGGAAA 1727 UUUCCUCAUUCAGCCUGAG siRNA 588 588 UCAGGCUGAAUGAGGAAAA 1728 UUUUCCUCAUUCAGCCUGA siRNA 589 589 CAGGCUGAAUGAGGAAAAA 1729 UUUUUCCUCAUUCAGCCUG siRNA 590 590 AGGCUGAAUGAGGAAAAAU 1730 AUUUUUCCUCAUUCAGCCU siRNA 591 591 GGCUGAAUGAGGAAAAAUU 1731 AAUUUUUCCUCAUUCAGCC siRNA 592 592 GCUGAAUGAGGAAAAAUUA 1732 UAAUUUUUCCUCAUUCAGC siRNA 593 593 CUGAAUGAGGAAAAAUUAU 1733 AUAAUUUUUCCUCAUUCAG siRNA 594 594 UGAAUGAGGAAAAAUUAUG 1734 CAUAAUUUUUCCUCAUUCA siRNA 595 595 GAAUGAGGAAAAAUUAUGG 1735 CCAUAAUUUUUCCUCAUUC siRNA 596 596 AAUGAGGAAAAAUUAUGGA 1736 UCCAUAAUUUUUCCUCAUU siRNA 597 597 AUGAGGAAAAAUUAUGGAA 1737 UUCCAUAAUUUUUCCUCAU siRNA 598 598 UGAGGAAAAAUUAUGGAAG 1738 CUUCCAUAAUUUUUCCUCA siRNA 599 599 GAGGAAAAAUUAUGGAAGA 1739 UCUUCCAUAAUUUUUCCUC siRNA 600 600 AGGAAAAAUUAUGGAAGAA 1740 UUCUUCCAUAAUUUUUCCU siRNA 601 601 GGAAAAAUUAUGGAAGAAA 1741 UUUCUUCCAUAAUUUUUCC siRNA 602 602 GAAAAAUUAUGGAAGAAAA 1742 UUUUCUUCCAUAAUUUUUC siRNA 603 603 AAAAAUUAUGGAAGAAAAG 1743 CUUUUCUUCCAUAAUUUUU siRNA 604 604 AAAAUUAUGGAAGAAAAGC 1744 GCUUUUCUUCCAUAAUUUU siRNA 605 605 AAAUUAUGGAAGAAAAGCA 1745 UGCUUUUCUUCCAUAAUUU siRNA 606 606 AAUUAUGGAAGAAAAGCAG 1746 CUGCUUUUCUUCCAUAAUU siRNA 607 607 AUUAUGGAAGAAAAGCAGA 1747 UCUGCUUUUCUUCCAUAAU siRNA 608 608 UUAUGGAAGAAAAGCAGAA 1748 UUCUGCUUUUCUUCCAUAA siRNA 609 609 UAUGGAAGAAAAGCAGAAC 1749 GUUCUGCUUUUCUUCCAUA siRNA 610 610 AUGGAAGAAAAGCAGAACG 1750 CGUUCUGCUUUUCUUCCAU siRNA 611 611 UGGAAGAAAAGCAGAACGG 1751 CCGUUCUGCUUUUCUUCCA siRNA 612 612 GGAAGAAAAGCAGAACGGU 1752 ACCGUUCUGCUUUUCUUCC siRNA 613 613 GAAGAAAAGCAGAACGGUG 1753 CACCGUUCUGCUUUUCUUC siRNA 614 614 AAGAAAAGCAGAACGGUGA 1754 UCACCGUUCUGCUUUUCUU siRNA 615 615 AGAAAAGCAGAACGGUGAA 1755 UUCACCGUUCUGCUUUUCU siRNA 616 616 GAAAAGCAGAACGGUGAAA 1756 UUUCACCGUUCUGCUUUUC siRNA 617 617 AAAAGCAGAACGGUGAAAG 1757 CUUUCACCGUUCUGCUUUU siRNA 618 618 AAAGCAGAACGGUGAAAGU 1758 ACUUUCACCGUUCUGCUUU siRNA 619 619 AAGCAGAACGGUGAAAGUG 1759 CACUUUCACCGUUCUGCUU siRNA 620 620 AGCAGAACGGUGAAAGUGG 1760 CCACUUUCACCGUUCUGCU siRNA 621 621 GCAGAACGGUGAAAGUGGG 1761 CCCACUUUCACCGUUCUGC siRNA 622 622 CAGAACGGUGAAAGUGGGA 1762 UCCCACUUUCACCGUUCUG siRNA 623 623 AGAACGGUGAAAGUGGGAG 1763 CUCCCACUUUCACCGUUCU siRNA 624 624 GAACGGUGAAAGUGGGAGA 1764 UCUCCCACUUUCACCGUUC siRNA 625 625 AACGGUGAAAGUGGGAGAU 1765 AUCUCCCACUUUCACCGUU siRNA 626 626 ACGGUGAAAGUGGGAGAUA 1766 UAUCUCCCACUUUCACCGU siRNA 627 627 CGGUGAAAGUGGGAGAUAC 1767 GUAUCUCCCACUUUCACCG siRNA 628 628 GGUGAAAGUGGGAGAUACA 1768 UGUAUCUCCCACUUUCACC siRNA 629 629 GUGAAAGUGGGAGAUACAU 1769 AUGUAUCUCCCACUUUCAC siRNA 630 630 UGAAAGUGGGAGAUACAUU 1770 AAUGUAUCUCCCACUUUCA siRNA 631 631 GAAAGUGGGAGAUACAUUG 1771 CAAUGUAUCUCCCACUUUC siRNA 632 632 AAAGUGGGAGAUACAUUGG 1772 CCAAUGUAUCUCCCACUUU siRNA 633 633 AAGUGGGAGAUACAUUGGA 1773 UCCAAUGUAUCUCCCACUU siRNA 634 634 AGUGGGAGAUACAUUGGAU 1774 AUCCAAUGUAUCUCCCACU siRNA 635 635 GUGGGAGAUACAUUGGAUC 1775 GAUCCAAUGUAUCUCCCAC siRNA 636 636 UGGGAGAUACAUUGGAUCU 1776 AGAUCCAAUGUAUCUCCCA siRNA 637 637 GGGAGAUACAUUGGAUCUU 1777 AAGAUCCAAUGUAUCUCCC siRNA 638 638 GGAGAUACAUUGGAUCUUC 1778 GAAGAUCCAAUGUAUCUCC siRNA 639 639 GAGAUACAUUGGAUCUUCU 1779 AGAAGAUCCAAUGUAUCUC siRNA 640 640 AGAUACAUUGGAUCUUCUC 1780 GAGAAGAUCCAAUGUAUCU siRNA 641 641 GAUACAUUGGAUCUUCUCA 1781 UGAGAAGAUCCAAUGUAUC siRNA 642 642 AUACAUUGGAUCUUCUCAU 1782 AUGAGAAGAUCCAAUGUAU siRNA 643 643 UACAUUGGAUCUUCUCAUU 1783 AAUGAGAAGAUCCAAUGUA siRNA 644 644 ACAUUGGAUCUUCUCAUUG 1784 CAAUGAGAAGAUCCAAUGU siRNA 645 645 CAUUGGAUCUUCUCAUUGG 1785 CCAAUGAGAAGAUCCAAUG siRNA 646 646 AUUGGAUCUUCUCAUUGGA 1786 UCCAAUGAGAAGAUCCAAU siRNA 647 647 UUGGAUCUUCUCAUUGGAG 1787 CUCCAAUGAGAAGAUCCAA siRNA 648 648 UGGAUCUUCUCAUUGGAGA 1788 UCUCCAAUGAGAAGAUCCA siRNA 649 649 GGAUCUUCUCAUUGGAGAG 1789 CUCUCCAAUGAGAAGAUCC siRNA 650 650 GAUCUUCUCAUUGGAGAGG 1790 CCUCUCCAAUGAGAAGAUC siRNA 651 651 AUCUUCUCAUUGGAGAGGA 1791 UCCUCUCCAAUGAGAAGAU siRNA 652 652 UCUUCUCAUUGGAGAGGAU 1792 AUCCUCUCCAAUGAGAAGA siRNA 653 653 CUUCUCAUUGGAGAGGAUA 1793 UAUCCUCUCCAAUGAGAAG siRNA 654 654 UUCUCAUUGGAGAGGAUAA 1794 UUAUCCUCUCCAAUGAGAA siRNA 655 655 UCUCAUUGGAGAGGAUAAA 1795 UUUAUCCUCUCCAAUGAGA siRNA 656 656 CUCAUUGGAGAGGAUAAAG 1796 CUUUAUCCUCUCCAAUGAG siRNA 657 657 UCAUUGGAGAGGAUAAAGA 1797 UCUUUAUCCUCUCCAAUGA siRNA 658 658 CAUUGGAGAGGAUAAAGAA 1798 UUCUUUAUCCUCUCCAAUG siRNA 659 659 AUUGGAGAGGAUAAAGAAG 1799 CUUCUUUAUCCUCUCCAAU siRNA 660 660 UUGGAGAGGAUAAAGAAGC 1800 GCUUCUUUAUCCUCUCCAA siRNA 661 661 UGGAGAGGAUAAAGAAGCA 1801 UGCUUCUUUAUCCUCUCCA siRNA 662 662 GGAGAGGAUAAAGAAGCAG 1802 CUGCUUCUUUAUCCUCUCC SiRNA 663 663 GAGAGGAUAAAGAAGCAGG 1803 CCUGCUUCUUUAUCCUCUC siRNA 664 664 AGAGGAUAAAGAAGCAGGA 1804 UCCUGCUUCUUUAUCCUCU siRNA 665 665 GAGGAUAAAGAAGCAGGAA 1805 UUCCUGCUUCUUUAUCCUC siRNA 666 666 AGGAUAAAGAAGCAGGAAC 1806 GUUCCUGCUUCUUUAUCCU siRNA 667 667 GGAUAAAGAAGCAGGAACA 1807 UGUUCCUGCUUCUUUAUCC siRNA 668 668 GAUAAAGAAGCAGGAACAG 1808 CUGUUCCUGCUUCUUUAUC siRNA 669 669 AUAAAGAAGCAGGAACAGA 1809 UCUGUUCCUGCUUCUUUAU siRNA 670 670 UAAAGAAGCAGGAACAGAG 1810 CUCUGUUCCUGCUUCUUUA siRNA 671 671 AAAGAAGCAGGAACAGAGA 1811 UCUCUGUUCCUGCUUCUUU siRNA 672 672 AAGAAGCAGGAACAGAGAC 1812 GUCUCUGUUCCUGCUUCUU siRNA 673 673 AGAAGCAGGAACAGAGACA 1813 UGUCUCUGUUCCUGCUUCU siRNA 674 674 GAAGCAGGAACAGAGACAG 1814 CUGUCUCUGUUCCUGCUUC siRNA 675 675 AAGCAGGAACAGAGACAGU 1815 ACUGUCUCUGUUCCUGCUU siRNA 676 676 AGCAGGAACAGAGACAGUU 1816 AACUGUCUCUGUUCCUGCU siRNA 677 677 GCAGGAACAGAGACAGUUA 1817 UAACUGUCUCUGUUCCUGC siRNA 678 678 CAGGAACAGAGACAGUUAU 1818 AUAACUGUCUCUGUUCCUG siRNA 679 679 AGGAACAGAGACAGUUAUG 1819 CAUAACUGUCUCUGUUCCU siRNA 680 680 GGAACAGAGACAGUUAUGC 1820 GCAUAACUGUCUCUGUUCC siRNA 681 681 GAACAGAGACAGUUAUGCG 1821 CGCAUAACUGUCUCUGUUC siRNA 682 682 AACAGAGACAGUUAUGCGG 1822 CCGCAUAACUGUCUCUGUU siRNA 683 683 ACAGAGACAGUUAUGCGGA 1823 UCCGCAUAACUGUCUCUGU siRNA 684 684 CAGAGACAGUUAUGCGGAU 1824 AUCCGCAUAACUGUCUCUG siRNA 685 685 AGAGACAGUUAUGCGGAUU 1825 AAUCCGCAUAACUGUCUCU siRNA 686 686 GAGACAGUUAUGCGGAUUC 1826 GAAUCCGCAUAACUGUCUC siRNA 687 687 AGACAGUUAUGCGGAUUCU 1827 AGAAUCCGCAUAACUGUCU siRNA 688 688 GACAGUUAUGCGGAUUCUC 1828 GAGAAUCCGCAUAACUGUC siRNA 689 689 ACAGUUAUGCGGAUUCUCU 1829 AGAGAAUCCGCAUAACUGU siRNA 690 690 CAGUUAUGCGGAUUCUCUU 1830 AAGAGAAUCCGCAUAACUG siRNA 691 691 AGUUAUGCGGAUUCUCUUG 1831 CAAGAGAAUCCGCAUAACU siRNA 692 692 GUUAUGCGGAUUCUCUUGA 1832 UCAAGAGAAUCCGCAUAAC siRNA 693 693 UUAUGCGGAUUCUCUUGAA 1833 UUCAAGAGAAUCCGCAUAA siRNA 694 694 UAUGCGGAUUCUCUUGAAA 1834 UUUCAAGAGAAUCCGCAUA siRNA 695 695 AUGCGGAUUCUCUUGAAAA 1835 UUUUCAAGAGAAUCCGCAU siRNA 696 696 UGCGGAUUCUCUUGAAAAA 1836 UUUUUCAAGAGAAUCCGCA siRNA 697 697 GCGGAUUCUCUUGAAAAAA 1837 UUUUUUCAAGAGAAUCCGC siRNA 698 698 CGGAUUCUCUUGAAAAAAG 1838 CUUUUUUCAAGAGAAUCCG siRNA 699 699 GGAUUCUCUUGAAAAAAGU 1839 ACUUUUUUCAAGAGAAUCC siRNA 700 700 GAUUCUCUUGAAAAAAGUG 1840 CACUUUUUUCAAGAGAAUC siRNA 701 701 AUUCUCUUGAAAAAAGUGU 1841 ACACUUUUUUCAAGAGAAU siRNA 702 702 UUCUCUUGAAAAAAGUGUU 1842 AACACUUUUUUCAAGAGAA siRNA 703 703 UCUCUUGAAAAAAGUGUUU 1843 AAACACUUUUUUCAAGAGA siRNA 704 704 CUCUUGAAAAAAGUGUUUG 1844 CAAACACUUUUUUCAAGAG siRNA 705 705 UCUUGAAAAAAGUGUUUGA 1845 UCAAACACUUUUUUCAAGA siRNA 706 706 CUUGAAAAAAGUGUUUGAA 1846 UUCAAACACUUUUUUCAAG siRNA 707 707 UUGAAAAAAGUGUUUGAAG 1847 CUUCAAACACUUUUUUCAA siRNA 708 708 UGAAAAAAGUGUUUGAAGA 1848 UCUUCAAACACUUUUUUCA siRNA 709 709 GAAAAAAGUGUUUGAAGAG 1849 CUCUUCAAACACUUUUUUC siRNA 710 710 AAAAAAGUGUUUGAAGAGA 1850 UCUCUUCAAACACUUUUUU siRNA 711 711 AAAAAGUGUUUGAAGAGAA 1851 UUCUCUUCAAACACUUUUU siRNA 712 712 AAAAGUGUUUGAAGAGAAG 1852 CUUCUCUUCAAACACUUUU siRNA 713 713 AAAGUGUUUGAAGAGAAGA 1853 UCUUCUCUUCAAACACUUU siRNA 714 714 AAGUGUUUGAAGAGAAGAC 1854 GUCUUCUCUUCAAACACUU siRNA 715 715 AGUGUUUGAAGAGAAGACU 1855 AGUCUUCUCUUCAAACACU siRNA 716 716 GUGUUUGAAGAGAAGACUG 1856 CAGUCUUCUCUUCAAACAC siRNA 717 717 UGUUUGAAGAGAAGACUGA 1857 UCAGUCUUCUCUUCAAACA siRNA 718 718 GUUUGAAGAGAAGACUGAA 1858 UUCAGUCUUCUCUUCAAAC siRNA 719 719 UUUGAAGAGAAGACUGAAA 1859 UUUCAGUCUUCUCUUCAAA siRNA 720 720 UUGAAGAGAAGACUGAAAG 1860 CUUUCAGUCUUCUCUUCAA siRNA 721 721 UGAAGAGAAGACUGAAAGU 1861 ACUUUCAGUCUUCUCUUCA siRNA 722 722 GAAGAGAAGACUGAAAGUG 1862 CACUUUCAGUCUUCUCUUC siRNA 723 723 AAGAGAAGACUGAAAGUGA 1863 UCACUUUCAGUCUUCUCUU siRNA 724 724 AGAGAAGACUGAAAGUGAA 1864 UUCACUUUCAGUCUUCUCU siRNA 725 725 GAGAAGACUGAAAGUGAAA 1865 UUUCACUUUCAGUCUUCUC siRNA 726 726 AGAAGACUGAAAGUGAAAA 1866 UUUUCACUUUCAGUCUUCU siRNA 727 727 GAAGACUGAAAGUGAAAAA 1867 UUUUUCACUUUCAGUCUUC siRNA 728 728 AAGACUGAAAGUGAAAAAU 1868 AUUUUUCACUUUCAGUCUU siRNA 729 729 AGACUGAAAGUGAAAAAUA 1869 UAUUUUUCACUUUCAGUCU siRNA 730 730 GACUGAAAGUGAAAAAUAC 1870 GUAUUUUUCACUUUCAGUC siRNA 731 731 ACUGAAAGUGAAAAAUACA 1871 UGUAUUUUUCACUUUCAGU siRNA 732 732 CUGAAAGUGAAAAAUACAG 1872 CUGUAUUUUUCACUUUCAG siRNA 733 733 UGAAAGUGAAAAAUACAGA 1873 UCUGUAUUUUUCACUUUCA siRNA 734 734 GAAAGUGAAAAAUACAGAG 1874 CUCUGUAUUUUUCACUUUC siRNA 735 735 AAAGUGAAAAAUACAGAGU 1875 ACUCUGUAUUUUUCACUUU siRNA 736 736 AAGUGAAAAAUACAGAGUG 1876 CACUCUGUAUUUUUCACUU siRNA 737 737 AGUGAAAAAUACAGAGUGG 1877 CCACUCUGUAUUUUUCACU siRNA 738 738 GUGAAAAAUACAGAGUGGU 1878 ACCACUCUGUAUUUUUCAC siRNA 739 739 UGAAAAAUACAGAGUGGUG 1879 CACCACUCUGUAUUUUUCA siRNA 740 740 GAAAAAUACAGAGUGGUGU 1880 ACACCACUCUGUAUUUUUC siRNA 741 741 AAAAAUACAGAGUGGUGUU 1881 AACACCACUCUGUAUUUUU siRNA 742 742 AAAAUACAGAGUGGUGUUA 1882 UAACACCACUCUGUAUUUU siRNA 743 743 AAAUACAGAGUGGUGUUAC 1883 GUAACACCACUCUGUAUUU siRNA 744 744 AAUACAGAGUGGUGUUACG 1884 CGUAACACCACUCUGUAUU siRNA 745 745 AUACAGAGUGGUGUUACGG 1885 CCGUAACACCACUCUGUAU siRNA 746 746 UACAGAGUGGUGUUACGGC 1886 GCCGUAACACCACUCUGUA siRNA 747 747 ACAGAGUGGUGUUACGGCG 1887 CGCCGUAACACCACUCUGU siRNA 748 748 CAGAGUGGUGUUACGGCGG 1888 CCGCCGUAACACCACUCUG siRNA 749 749 AGAGUGGUGUUACGGCGGU 1889 ACCGCCGUAACACCACUCU siRNA 750 750 GAGUGGUGUUACGGCGGUG 1890 CACCGCCGUAACACCACUC siRNA 751 751 AGUGGUGUUACGGCGGUGG 1891 CCACCGCCGUAACACCACU siRNA 752 752 GUGGUGUUACGGCGGUGGA 1892 UCCACCGCCGUAACACCAC siRNA 753 753 UGGUGUUACGGCGGUGGAA 1893 UUCCACCGCCGUAACACCA siRNA 754 754 GGUGUUACGGCGGUGGAAA 1894 UUUCCACCGCCGUAACACC siRNA 755 755 GUGUUACGGCGGUGGAAAA 1895 UUUUCCACCGCCGUAACAC siRNA 756 756 UGUUACGGCGGUGGAAAAG 1896 CUUUUCCACCGCCGUAACA siRNA 757 757 GUUACGGCGGUGGAAAAGU 1897 ACUUUUCCACCGCCGUAAC siRNA 758 758 UUACGGCGGUGGAAAAGUU 1898 AACUUUUCCACCGCCGUAA siRNA 759 759 UACGGCGGUGGAAAAGUUU 1899 AAACUUUUCCACCGCCGUA siRNA 760 760 ACGGCGGUGGAAAAGUUUA 1900 UAAACUUUUCCACCGCCGU siRNA 761 761 CGGCGGUGGAAAAGUUUAA 1901 UUAAACUUUUCCACCGCCG siRNA 762 762 GGCGGUGGAAAAGUUUAAA 1902 UUUAAACUUUUCCACCGCC siRNA 763 763 GCGGUGGAAAAGUUUAAAG 1903 CUUUAAACUUUUCCACCGC siRNA 764 764 CGGUGGAAAAGUUUAAAGU 1904 ACUUUAAACUUUUCCACCG siRNA 765 765 GGUGGAAAAGUUUAAAGUU 1905 AACUUUAAACUUUUCCACC siRNA 766 766 GUGGAAAAGUUUAAAGUUG 1906 CAACUUUAAACUUUUCCAC siRNA 767 767 UGGAAAAGUUUAAAGUUGC 1907 GCAACUUUAAACUUUUCCA siRNA 768 768 GGAAAAGUUUAAAGUUGCC 1908 GGCAACUUUAAACUUUUCC siRNA 769 769 GAAAAGUUUAAAGUUGCCU 1909 AGGCAACUUUAAACUUUUC siRNA 770 770 AAAAGUUUAAAGUUGCCUA 1910 UAGGCAACUUUAAACUUUU siRNA 771 771 AAAGUUUAAAGUUGCCUAA 1911 UUAGGCAACUUUAAACUUU siRNA 772 772 AAGUUUAAAGUUGCCUAAG 1912 CUUAGGCAACUUUAAACUU siRNA 773 773 AGUUUAAAGUUGCCUAAGA 1913 UCUUAGGCAACUUUAAACU siRNA 774 774 GUUUAAAGUUGCCUAAGAA 1914 UUCUUAGGCAACUUUAAAC siRNA 775 775 UUUAAAGUUGCCUAAGAAG 1915 CUUCUUAGGCAACUUUAAA siRNA 776 776 UUAAAGUUGCCUAAGAAGA 1916 UCUUCUUAGGCAACUUUAA siRNA 777 777 UAAAGUUGCCUAAGAAGAG 1917 CUCUUCUUAGGCAACUUUA siRNA 778 778 AAAGUUGCCUAAGAAGAGA 1918 UCUCUUCUUAGGCAACUUU siRNA 779 779 AAGUUGCCUAAGAAGAGAA 1919 UUCUCUUCUUAGGCAACUU siRNA 780 780 AGUUGCCUAAGAAGAGAAU 1920 AUUCUCUUCUUAGGCAACU siRNA 781 781 GUUGCCUAAGAAGAGAAUG 1921 CAUUCUCUUCUUAGGCAAC siRNA 782 782 UUGCCUAAGAAGAGAAUGU 1922 ACAUUCUCUUCUUAGGCAA siRNA 783 783 UGCCUAAGAAGAGAAUGUC 1923 GACAUUCUCUUCUUAGGCA siRNA 784 784 GCCUAAGAAGAGAAUGUCU 1924 AGACAUUCUCUUCUUAGGC siRNA 785 785 CCUAAGAAGAGAAUGUCUA 1925 UAGACAUUCUCUUCUUAGG siRNA 786 786 CUAAGAAGAGAAUGUCUAA 1926 UUAGACAUUCUCUUCUUAG siRNA 787 787 UAAGAAGAGAAUGUCUAAA 1927 UUUAGACAUUCUCUUCUUA siRNA 788 788 AAGAAGAGAAUGUCUAAAU 1928 AUUUAGACAUUCUCUUCUU siRNA 789 789 AGAAGAGAAUGUCUAAAUA 1929 UAUUUAGACAUUCUCUUCU siRNA 790 790 GAAGAGAAUGUCUAAAUAA 1930 UUAUUUAGACAUUCUCUUC siRNA 791 791 AAGAGAAUGUCUAAAUAAA 1931 UUUAUUUAGACAUUCUCUU siRNA 792 792 AGAGAAUGUCUAAAUAAAU 1932 AUUUAUUUAGACAUUCUCU siRNA 793 793 GAGAAUGUCUAAAUAAAUG 1933 CAUUUAUUUAGACAUUCUC siRNA 794 794 AGAAUGUCUAAAUAAAUGG 1934 CCAUUUAUUUAGACAUUCU siRNA 795 795 GAAUGUCUAAAUAAAUGGA 1935 UCCAUUUAUUUAGACAUUC siRNA 796 796 AAUGUCUAAAUAAAUGGAU 1936 AUCCAUUUAUUUAGACAUU siRNA 797 797 AUGUCUAAAUAAAUGGAUU 1937 AAUCCAUUUAUUUAGACAU siRNA 798 798 UGUCUAAAUAAAUGGAUUG 1938 CAAUCCAUUUAUUUAGACA siRNA 799 799 GUCUAAAUAAAUGGAUUGC 1939 GCAAUCCAUUUAUUUAGAC siRNA 800 800 UCUAAAUAAAUGGAUUGCU 1940 AGCAAUCCAUUUAUUUAGA siRNA 801 801 CUAAAUAAAUGGAUUGCUU 1941 AAGCAAUCCAUUUAUUUAG siRNA 802 802 UAAAUAAAUGGAUUGCUUU 1942 AAAGCAAUCCAUUUAUUUA siRNA 803 803 AAAUAAAUGGAUUGCUUUU 1943 AAAAGCAAUCCAUUUAUUU siRNA 804 804 AAUAAAUGGAUUGCUUUUU 1944 AAAAAGCAAUCCAUUUAUU siRNA 805 805 AUAAAUGGAUUGCUUUUUA 1945 UAAAAAGCAAUCCAUUUAU siRNA 806 806 UAAAUGGAUUGCUUUUUAG 1946 CUAAAAAGCAAUCCAUUUA siRNA 807 807 AAAUGGAUUGCUUUUUAGC 1947 GCUAAAAAGCAAUCCAUUU siRNA 808 808 AAUGGAUUGCUUUUUAGCA 1948 UGCUAAAAAGCAAUCCAUU siRNA 809 809 AUGGAUUGCUUUUUAGCAA 1949 UUGCUAAAAAGCAAUCCAU siRNA 810 810 UGGAUUGCUUUUUAGCAAU 1950 AUUGCUAAAAAGCAAUCCA siRNA 811 811 GGAUUGCUUUUUAGCAAUA 1951 UAUUGCUAAAAAGCAAUCC siRNA 812 812 GAUUGCUUUUUAGCAAUAG 1952 CUAUUGCUAAAAAGCAAUC siRNA 813 813 AUUGCUUUUUAGCAAUAGA 1953 UCUAUUGCUAAAAAGCAAU siRNA 814 814 UUGCUUUUUAGCAAUAGAG 1954 CUCUAUUGCUAAAAAGCAA siRNA 815 815 UGCUUUUUAGCAAUAGAGC 1955 GCUCUAUUGCUAAAAAGCA siRNA 816 816 GCUUUUUAGCAAUAGAGCU 1956 AGCUCUAUUGCUAAAAAGC siRNA 817 817 CUUUUUAGCAAUAGAGCUG 1957 CAGCUCUAUUGCUAAAAAG siRNA 818 818 UUUUUAGCAAUAGAGCUGC 1958 GCAGCUCUAUUGCUAAAAA siRNA 819 819 UUUUAGCAAUAGAGCUGCU 1959 AGCAGCUCUAUUGCUAAAA siRNA 820 820 UUUAGCAAUAGAGCUGCUU 1960 AAGCAGCUCUAUUGCUAAA siRNA 821 821 UUAGCAAUAGAGCUGCUUU 1961 AAAGCAGCUCUAUUGCUAA siRNA 822 822 UAGCAAUAGAGCUGCUUUC 1962 GAAAGCAGCUCUAUUGCUA siRNA 823 823 AGCAAUAGAGCUGCUUUCU 1963 AGAAAGCAGCUCUAUUGCU siRNA 824 824 GCAAUAGAGCUGCUUUCUA 1964 UAGAAAGCAGCUCUAUUGC siRNA 825 825 CAAUAGAGCUGCUUUCUAG 1965 CUAGAAAGCAGCUCUAUUG siRNA 826 826 AAUAGAGCUGCUUUCUAGU 1966 ACUAGAAAGCAGCUCUAUU siRNA 827 827 AUAGAGCUGCUUUCUAGUG 1967 CACUAGAAAGCAGCUCUAU siRNA 828 828 UAGAGCUGCUUUCUAGUGG 1968 CCACUAGAAAGCAGCUCUA siRNA 829 829 AGAGCUGCUUUCUAGUGGU 1969 ACCACUAGAAAGCAGCUCU siRNA 830 830 GAGCUGCUUUCUAGUGGUA 1970 UACCACUAGAAAGCAGCUC siRNA 831 831 AGCUGCUUUCUAGUGGUAA 1971 UUACCACUAGAAAGCAGCU siRNA 832 832 GCUGCUUUCUAGUGGUAAA 1972 UUUACCACUAGAAAGCAGC siRNA 833 833 CUGCUUUCUAGUGGUAAAG 1973 CUUUACCACUAGAAAGCAG siRNA 834 834 UGCUUUCUAGUGGUAAAGG 1974 CCUUUACCACUAGAAAGCA siRNA 835 835 GCUUUCUAGUGGUAAAGGA 1975 UCCUUUACCACUAGAAAGC siRNA 836 836 CUUUCUAGUGGUAAAGGAA 1976 UUCCUUUACCACUAGAAAG siRNA 837 837 UUUCUAGUGGUAAAGGAAG 1977 CUUCCUUUACCACUAGAAA siRNA 838 838 UUCUAGUGGUAAAGGAAGG 1978 CCUUCCUUUACCACUAGAA siRNA 839 839 UCUAGUGGUAAAGGAAGGG 1979 CCCUUCCUUUACCACUAGA siRNA 840 840 CUAGUGGUAAAGGAAGGGG 1980 CCCCUUCCUUUACCACUAG siRNA 841 841 UAGUGGUAAAGGAAGGGGU 1981 ACCCCUUCCUUUACCACUA siRNA 842 842 AGUGGUAAAGGAAGGGGUC 1982 GACCCCUUCCUUUACCACU siRNA 843 843 GUGGUAAAGGAAGGGGUCA 1983 UGACCCCUUCCUUUACCAC siRNA 844 844 UGGUAAAGGAAGGGGUCAC 1984 GUGACCCCUUCCUUUACCA siRNA 845 845 GGUAAAGGAAGGGGUCACC 1985 GGUGACCCCUUCCUUUACC siRNA 846 846 GUAAAGGAAGGGGUCACCU 1986 AGGUGACCCCUUCCUUUAC siRNA 847 847 UAAAGGAAGGGGUCACCUG 1987 CAGGUGACCCCUUCCUUUA siRNA 848 848 AAAGGAAGGGGUCACCUGA 1988 UCAGGUGACCCCUUCCUUU siRNA 849 849 AAGGAAGGGGUCACCUGAA 1989 UUCAGGUGACCCCUUCCUU siRNA 850 850 AGGAAGGGGUCACCUGAAA 1990 UUUCAGGUGACCCCUUCCU siRNA 851 851 GGAAGGGGUCACCUGAAAA 1991 UUUUCAGGUGACCCCUUCC siRNA 852 852 GAAGGGGUCACCUGAAAAA 1992 UUUUUCAGGUGACCCCUUC siRNA 853 853 AAGGGGUCACCUGAAAAAU 1993 AUUUUUCAGGUGACCCCUU siRNA 854 854 AGGGGUCACCUGAAAAAUA 1994 UAUUUUUCAGGUGACCCCU siRNA 855 855 GGGGUCACCUGAAAAAUAG 1995 CUAUUUUUCAGGUGACCCC siRNA 856 856 GGGUCACCUGAAAAAUAGG 1996 CCUAUUUUUCAGGUGACCC siRNA 857 857 GGUCACCUGAAAAAUAGGA 1997 UCCUAUUUUUCAGGUGACC siRNA 858 858 GUCACCUGAAAAAUAGGAC 1998 GUCCUAUUUUUCAGGUGAC siRNA 859 859 UCACCUGAAAAAUAGGACA 1999 UGUCCUAUUUUUCAGGUGA siRNA 860 860 CACCUGAAAAAUAGGACAU 2000 AUGUCCUAUUUUUCAGGUG siRNA 861 861 ACCUGAAAAAUAGGACAUU 2001 AAUGUCCUAUUUUUCAGGU siRNA 862 862 CCUGAAAAAUAGGACAUUU 2002 AAAUGUCCUAUUUUUCAGG SIRNA 863 863 CUGAAAAAUAGGACAUUUU 2003 AAAAUGUCCUAUUUUUCAG siRNA 864 864 UGAAAAAUAGGACAUUUUU 2004 AAAAAUGUCCUAUUUUUCA siRNA 865 865 GAAAAAUAGGACAUUUUUA 2005 UAAAAAUGUCCUAUUUUUC siRNA 866 866 AAAAAUAGGACAUUUUUAU 2006 AUAAAAAUGUCCUAUUUUU siRNA 867 867 AAAAUAGGACAUUUUUAUU 2007 AAUAAAAAUGUCCUAUUUU siRNA 868 868 AAAUAGGACAUUUUUAUUA 2008 UAAUAAAAAUGUCCUAUUU siRNA 869 869 AAUAGGACAUUUUUAUUAA 2009 UUAAUAAAAAUGUCCUAUU siRNA 870 870 AUAGGACAUUUUUAUUAAA 2010 UUUAAUAAAAAUGUCCUAU siRNA 871 871 UAGGACAUUUUUAUUAAAA 2011 UUUUAAUAAAAAUGUCCUA siRNA 872 872 AGGACAUUUUUAUUAAAAU 2012 AUUUUAAUAAAAAUGUCCU siRNA 873 873 GGACAUUUUUAUUAAAAUA 2013 UAUUUUAAUAAAAAUGUCC siRNA 874 874 GACAUUUUUAUUAAAAUAA 2014 UUAUUUUAAUAAAAAUGUC siRNA 875 875 ACAUUUUUAUUAAAAUAAA 2015 UUUAUUUUAAUAAAAAUGU siRNA 876 876 CAUUUUUAUUAAAAUAAAG 2016 CUUUAUUUUAAUAAAAAUG siRNA 877 877 AUUUUUAUUAAAAUAAAGU 2017 ACUUUAUUUUAAUAAAAAU siRNA 878 878 UUUUUAUUAAAAUAAAGUU 2018 AACUUUAUUUUAAUAAAAA siRNA 879 879 UUUUAUUAAAAUAAAGUUC 2019 GAACUUUAUUUUAAUAAAA siRNA 880 880 UUUAUUAAAAUAAAGUUCU 2020 AGAACUUUAUUUUAAUAAA siRNA 881 881 UUAUUAAAAUAAAGUUCUC 2021 GAGAACUUUAUUUUAAUAA siRNA 882 882 UAUUAAAAUAAAGUUCUCU 2022 AGAGAACUUUAUUUUAAUA siRNA 883 883 AUUAAAAUAAAGUUCUCUU 2023 AAGAGAACUUUAUUUUAAU siRNA 884 884 UUAAAAUAAAGUUCUCUUA 2024 UAAGAGAACUUUAUUUUAA siRNA 885 885 UAAAAUAAAGUUCUCUUAG 2025 CUAAGAGAACUUUAUUUUA siRNA 886 886 AAAAUAAAGUUCUCUUAGC 2026 GCUAAGAGAACUUUAUUUU siRNA 887 887 AAAUAAAGUUCUCUUAGCG 2027 CGCUAAGAGAACUUUAUUU siRNA 888 888 AAUAAAGUUCUCUUAGCGU 2028 ACGCUAAGAGAACUUUAUU siRNA 889 889 AUAAAGUUCUCUUAGCGUU 2029 AACGCUAAGAGAACUUUAU siRNA 890 890 UAAAGUUCUCUUAGCGUUU 2030 AAACGCUAAGAGAACUUUA siRNA 891 891 AAAGUUCUCUUAGCGUUUG 2031 CAAACGCUAAGAGAACUUU siRNA 892 892 AAGUUCUCUUAGCGUUUGU 2032 ACAAACGCUAAGAGAACUU siRNA 893 893 AGUUCUCUUAGCGUUUGUG 2033 CACAAACGCUAAGAGAACU siRNA 894 894 GUUCUCUUAGCGUUUGUGG 2034 CCACAAACGCUAAGAGAAC siRNA 895 895 UUCUCUUAGCGUUUGUGGA 2035 UCCACAAACGCUAAGAGAA siRNA 896 896 UCUCUUAGCGUUUGUGGAA 2036 UUCCACAAACGCUAAGAGA siRNA 897 897 CUCUUAGCGUUUGUGGAAU 2037 AUUCCACAAACGCUAAGAG siRNA 898 898 UCUUAGCGUUUGUGGAAUC 2038 GAUUCCACAAACGCUAAGA siRNA 899 899 CUUAGCGUUUGUGGAAUCU 2039 AGAUUCCACAAACGCUAAG siRNA 900 900 UUAGCGUUUGUGGAAUCUG 2040 CAGAUUCCACAAACGCUAA siRNA 901 901 UAGCGUUUGUGGAAUCUGC 2041 GCAGAUUCCACAAACGCUA siRNA 902 902 AGCGUUUGUGGAAUCUGCC 2042 GGCAGAUUCCACAAACGCU siRNA 903 903 GCGUUUGUGGAAUCUGCCG 2043 CGGCAGAUUCCACAAACGC siRNA 904 904 CGUUUGUGGAAUCUGCCGA 2044 UCGGCAGAUUCCACAAACG siRNA 905 905 GUUUGUGGAAUCUGCCGAG 2045 CUCGGCAGAUUCCACAAAC siRNA 906 906 UUUGUGGAAUCUGCCGAGC 2046 GCUCGGCAGAUUCCACAAA siRNA 907 907 UUGUGGAAUCUGCCGAGCC 2047 GGCUCGGCAGAUUCCACAA siRNA 908 908 UGUGGAAUCUGCCGAGCCA 2048 UGGCUCGGCAGAUUCCACA siRNA 909 909 GUGGAAUCUGCCGAGCCAU 2049 AUGGCUCGGCAGAUUCCAC siRNA 910 910 UGGAAUCUGCCGAGCCAUU 2050 AAUGGCUCGGCAGAUUCCA siRNA 911 911 GGAAUCUGCCGAGCCAUUU 2051 AAAUGGCUCGGCAGAUUCC siRNA 912 912 GAAUCUGCCGAGCCAUUUU 2052 AAAAUGGCUCGGCAGAUUC siRNA 913 913 AAUCUGCCGAGCCAUUUUG 2053 CAAAAUGGCUCGGCAGAUU siRNA 914 914 AUCUGCCGAGCCAUUUUGU 2054 ACAAAAUGGCUCGGCAGAU siRNA 915 915 UCUGCCGAGCCAUUUUGUG 2055 CACAAAAUGGCUCGGCAGA siRNA 916 916 CUGCCGAGCCAUUUUGUGG 2056 CCACAAAAUGGCUCGGCAG siRNA 917 917 UGCCGAGCCAUUUUGUGGA 2057 UCCACAAAAUGGCUCGGCA siRNA 918 918 GCCGAGCCAUUUUGUGGAA 2058 UUCCACAAAAUGGCUCGGC siRNA 919 919 CCGAGCCAUUUUGUGGAAA 2059 UUUCCACAAAAUGGCUCGG siRNA 920 920 CGAGCCAUUUUGUGGAAAU 2060 AUUUCCACAAAAUGGCUCG siRNA 921 921 GAGCCAUUUUGUGGAAAUU 2061 AAUUUCCACAAAAUGGCUC siRNA 922 922 AGCCAUUUUGUGGAAAUUG 2062 CAAUUUCCACAAAAUGGCU siRNA 923 923 GCCAUUUUGUGGAAAUUGG 2063 CCAAUUUCCACAAAAUGGC siRNA 924 924 CCAUUUUGUGGAAAUUGGG 2064 CCCAAUUUCCACAAAAUGG siRNA 925 925 CAUUUUGUGGAAAUUGGGA 2065 UCCCAAUUUCCACAAAAUG siRNA 926 926 AUUUUGUGGAAAUUGGGAU 2066 AUCCCAAUUUCCACAAAAU siRNA 927 927 UUUUGUGGAAAUUGGGAUC 2067 GAUCCCAAUUUCCACAAAA siRNA 928 928 UUUGUGGAAAUUGGGAUCC 2068 GGAUCCCAAUUUCCACAAA siRNA 929 929 UUGUGGAAAUUGGGAUCCA 2069 UGGAUCCCAAUUUCCACAA siRNA 930 930 UGUGGAAAUUGGGAUCCAU 2070 AUGGAUCCCAAUUUCCACA siRNA 931 931 GUGGAAAUUGGGAUCCAUA 2071 UAUGGAUCCCAAUUUCCAC siRNA 932 932 UGGAAAUUGGGAUCCAUAU 2072 AUAUGGAUCCCAAUUUCCA siRNA 933 933 GGAAAUUGGGAUCCAUAUC 2073 GAUAUGGAUCCCAAUUUCC siRNA 934 934 GAAAUUGGGAUCCAUAUCU 2074 AGAUAUGGAUCCCAAUUUC siRNA 935 935 AAAUUGGGAUCCAUAUCUG 2075 CAGAUAUGGAUCCCAAUUU siRNA 936 936 AAUUGGGAUCCAUAUCUGG 2076 CCAGAUAUGGAUCCCAAUU siRNA 937 937 AUUGGGAUCCAUAUCUGGA 2077 UCCAGAUAUGGAUCCCAAU siRNA 938 938 UUGGGAUCCAUAUCUGGAG 2078 CUCCAGAUAUGGAUCCCAA siRNA 939 939 UGGGAUCCAUAUCUGGAGA 2079 UCUCCAGAUAUGGAUCCCA siRNA 940 940 GGGAUCCAUAUCUGGAGAC 2080 GUCUCCAGAUAUGGAUCCC siRNA 941 941 GGAUCCAUAUCUGGAGACA 2081 UGUCUCCAGAUAUGGAUCC siRNA 942 942 GAUCCAUAUCUGGAGACAC 2082 GUGUCUCCAGAUAUGGAUC siRNA 943 943 AUCCAUAUCUGGAGACACU 2083 AGUGUCUCCAGAUAUGGAU siRNA 944 944 UCCAUAUCUGGAGACACUU 2084 AAGUGUCUCCAGAUAUGGA siRNA 945 945 CCAUAUCUGGAGACACUUC 2085 GAAGUGUCUCCAGAUAUGG siRNA 946 946 CAUAUCUGGAGACACUUCC 2086 GGAAGUGUCUCCAGAUAUG siRNA 947 947 AUAUCUGGAGACACUUCCC 2087 GGGAAGUGUCUCCAGAUAU siRNA 948 948 UAUCUGGAGACACUUCCCA 2088 UGGGAAGUGUCUCCAGAUA siRNA 949 949 AUCUGGAGACACUUCCCAA 2089 UUGGGAAGUGUCUCCAGAU siRNA 950 950 UCUGGAGACACUUCCCAAG 2090 CUUGGGAAGUGUCUCCAGA siRNA 951 951 CUGGAGACACUUCCCAAGG 2091 CCUUGGGAAGUGUCUCCAG siRNA 952 952 UGGAGACACUUCCCAAGGC 2092 GCCUUGGGAAGUGUCUCCA siRNA 953 953 GGAGACACUUCCCAAGGCC 2093 GGCCUUGGGAAGUGUCUCC siRNA 954 954 GAGACACUUCCCAAGGCCU 2094 AGGCCUUGGGAAGUGUCUC siRNA 955 955 AGACACUUCCCAAGGCCUG 2095 CAGGCCUUGGGAAGUGUCU siRNA 956 956 GACACUUCCCAAGGCCUGC 2096 GCAGGCCUUGGGAAGUGUC siRNA 957 957 ACACUUCCCAAGGCCUGCC 2097 GGCAGGCCUUGGGAAGUGU siRNA 958 958 CACUUCCCAAGGCCUGCCU 2098 AGGCAGGCCUUGGGAAGUG siRNA 959 959 ACUUCCCAAGGCCUGCCUC 2099 GAGGCAGGCCUUGGGAAGU siRNA 960 960 CUUCCCAAGGCCUGCCUCA 2100 UGAGGCAGGCCUUGGGAAG siRNA 961 961 UUCCCAAGGCCUGCCUCAC 2101 GUGAGGCAGGCCUUGGGAA siRNA 962 962 UCCCAAGGCCUGCCUCACC 2102 GGUGAGGCAGGCCUUGGGA siRNA 963 963 CCCAAGGCCUGCCUCACCU 2103 AGGUGAGGCAGGCCUUGGG siRNA 964 964 CCAAGGCCUGCCUCACCUC 2104 GAGGUGAGGCAGGCCUUGG siRNA 965 965 CAAGGCCUGCCUCACCUCC 2105 GGAGGUGAGGCAGGCCUUG siRNA 966 966 AAGGCCUGCCUCACCUCCA 2106 UGGAGGUGAGGCAGGCCUU siRNA 967 967 AGGCCUGCCUCACCUCCAC 2107 GUGGAGGUGAGGCAGGCCU siRNA 968 968 GGCCUGCCUCACCUCCACC 2108 GGUGGAGGUGAGGCAGGCC siRNA 969 969 GCCUGCCUCACCUCCACCC 2109 GGGUGGAGGUGAGGCAGGC siRNA 970 970 CCUGCCUCACCUCCACCCC 2110 GGGGUGGAGGUGAGGCAGG siRNA 971 971 CUGCCUCACCUCCACCCCC 2111 GGGGGUGGAGGUGAGGCAG siRNA 972 972 UGCCUCACCUCCACCCCCU 2112 AGGGGGUGGAGGUGAGGCA siRNA 973 973 GCCUCACCUCCACCCCCUG 2113 CAGGGGGUGGAGGUGAGGC siRNA 974 974 CCUCACCUCCACCCCCUGC 2114 GCAGGGGGUGGAGGUGAGG siRNA 975 975 CUCACCUCCACCCCCUGCC 2115 GGCAGGGGGUGGAGGUGAG siRNA 976 976 UCACCUCCACCCCCUGCCC 2116 GGGCAGGGGGUGGAGGUGA siRNA 977 977 CACCUCCACCCCCUGCCCA 2117 UGGGCAGGGGGUGGAGGUG siRNA 978 978 ACCUCCACCCCCUGCCCAC 2118 GUGGGCAGGGGGUGGAGGU siRNA 979 979 CCUCCACCCCCUGCCCACC 2119 GGUGGGCAGGGGGUGGAGG siRNA 980 980 CUCCACCCCCUGCCCACCU 2120 AGGUGGGCAGGGGGUGGAG siRNA 981 981 UCCACCCCCUGCCCACCUU 2121 AAGGUGGGCAGGGUGUGGA siRNA 982 982 CCACCCCCUGCCCACCUUG 2122 CAAGGUGGGCAGGGGGUGG siRNA 983 983 CACCCCCUGCCCACCUUGA 2123 UCAAGGUGGGCAGGGGGUG siRNA 984 984 ACCCCCUGCCCACCUUGAU 2124 AUCAAGGUGGGCAGGGGGU siRNA 985 985 CCCCCUGCCCACCUUGAUC 2125 GAUCAAGGUGGGCAGGGGG siRNA 986 986 CCCCUGCCCACCUUGAUCC 2126 GGAUCAAGGUGGGCAGGGG siRNA 987 987 CCCUGCCCACCUUGAUCCA 2127 UGGAUCAAGGUGGGCAGGG siRNA 988 988 CCUGCCCACCUUGAUCCAU 2128 AUGGAUCAAGGUGGGCAGG siRNA 989 989 CUGCCCACCUUGAUCCAUG 2129 CAUGGAUCAAGGUGGGCAG siRNA 990 990 UGCCCACCUUGAUCCAUGC 2130 GCAUGGAUCAAGGUGGGCA siRNA 991 991 GCCCACCUUGAUCCAUGCU 2131 AGCAUGGAUCAAGGUGGGC siRNA 992 992 CCCACCUUGAUCCAUGCUC 2132 GAGCAUGGAUCAAGGUGGG siRNA 993 993 CCACCUUGAUCCAUGCUCC 2133 GGAGCAUGGAUCAAGGUGG siRNA 994 994 CACCUUGAUCCAUGCUCCU 2134 AGGAGCAUGGAUCAAGGUG siRNA 995 995 ACCUUGAUCCAUGCUCCUU 2135 AAGGAGCAUGGAUCAAGGU siRNA 996 996 CCUUGAUCCAUGCUCCUUU 2136 AAAGGAGCAUGGAUCAAGG siRNA 997 997 CUUGAUCCAUGCUCCUUUG 2137 CAAAGGAGCAUGGAUCAAG siRNA 998 998 UUGAUCCAUGCUCCUUUGA 2138 UCAAAGGAGCAUGGAUCAA siRNA 999 999 UGAUCCAUGCUCCUUUGAC 2139 GUCAAAGGAGCAUGGAUCA siRNA 1000 1000 GAUCCAUGCUCCUUUGACC 2140 GGUCAAAGGAGCAUGGAUC siRNA 1001 1001 AUCCAUGCUCCUUUGACCU 2141 AGGUCAAAGGAGCAUGGAU siRNA 1002 1002 UCCAUGCUCCUUUGACCUC 2142 GAGGUCAAAGGAGCAUGGA siRNA 1003 1003 CCAUGCUCCUUUGACCUCC 2143 GGAGGUCAAAGGAGCAUGG siRNA 1004 1004 CAUGCUCCUUUGACCUCCU 2144 AGGAGGUCAAAGGAGCAUG siRNA 1005 1005 AUGCUCCUUUGACCUCCUC 2145 GAGGAGGUCAAAGGAGCAU siRNA 1006 1006 UGCUCCUUUGACCUCCUCG 2146 CGAGGAGGUCAAAGGAGCA siRNA 1007 1007 GCUCCUUUGACCUCCUCGU 2147 ACGAGGAGGUCAAAGGAGC siRNA 1008 1008 CUCCUUUGACCUCCUCGUG 2148 CACGAGGAGGUCAAAGGAG siRNA 1009 1009 UCCUUUGACCUCCUCGUGU 2149 ACACGAGGAGGUCAAAGGA siRNA 1010 1010 CCUUUGACCUCCUCGUGUG 2150 CACACGAGGAGGUCAAAGG siRNA 1011 1011 CUUUGACCUCCUCGUGUGA 2151 UCACACGAGGAGGUCAAAG siRNA 1012 1012 UUUGACCUCCUCGUGUGAG 2152 CUCACACGAGGAGGUCAAA siRNA 1013 1013 UUGACCUCCUCGUGUGAGA 2153 UCUCACACGAGGAGGUCAA siRNA 1014 1014 UGACCUCCUCGUGUGAGAA 2154 UUCUCACACGAGGAGGUCA siRNA 1015 1015 GACCUCCUCGUGUGAGAAC 2155 GUUCUCACACGAGGAGGUC SIRNA 1016 1016 ACCUCCUCGUGUGAGAACC 2156 GGUUCUCACACGAGGAGGU siRNA 1017 1017 CCUCCUCGUGUGAGAACCC 2157 GGGUUCUCACACGAGGAGG siRNA 1018 1018 CUCCUCGUGUGAGAACCCC 2158 GGGGUUCUCACACGAGGAG SIRNA 1019 1019 UCCUCGUGUGAGAACCCCU 2159 AGGGGUUCUCACACGAGGA siRNA 1020 1020 CCUCGUGUGAGAACCCCUU 2160 AAGGGGUUCUCACACGAGG siRNA 1021 1021 CUCGUGUGAGAACCCCUUU 2161 AAAGGGGUUCUCACACGAG siRNA 1022 1022 UCGUGUGAGAACCCCUUUG 2162 CAAAGGGGUUCUCACACGA siRNA 1023 1023 CGUGUGAGAACCCCUUUGC 2163 GCAAAGGGGUUCUCACACG siRNA 1024 1024 GUGUGAGAACCCCUUUGCC 2164 GGCAAAGGGGUUCUCACAC siRNA 1025 1025 UGUGAGAACCCCUUUGCCA 2165 UGGCAAAGGGGUUCUCACA siRNA 1026 1026 GUGAGAACCCCUUUGCCAG 2166 CUGGCAAAGGGGUUCUCAC siRNA 1027 1027 UGAGAACCCCUUUGCCAGA 2167 UCUGGCAAAGGGGUUCUCA siRNA 1028 1028 GAGAACCCCUUUGCCAGAG 2168 CUCUGGCAAAGGGGUUCUC siRNA 1029 1029 AGAACCCCUUUGCCAGAGU 2169 ACUCUGGCAAAGGGGUUCU siRNA 1030 1030 GAACCCCUUUGCCAGAGUG 2170 CACUCUGGCAAAGGGGUUC siRNA 1031 1031 AACCCCUUUGCCAGAGUGA 2171 UCACUCUGGCAAAGGGGUU siRNA 1032 1032 ACCCCUUUGCCAGAGUGAG 2172 CUCACUCUGGCAAAGGGGU siRNA 1033 1033 CCCCUUUGCCAGAGUGAGA 2173 UCUCACUCUGGCAAAGGGG siRNA 1034 1034 CCCUUUGCCAGAGUGAGAC 2174 GUCUCACUCUGGCAAAGGG siRNA 1035 1035 CCUUUGCCAGAGUGAGACG 2175 CGUCUCACUCUGGCAAAGG siRNA 1036 1036 CUUUGCCAGAGUGAGACGU 2176 ACGUCUCACUCUGGCAAAG siRNA 1037 1037 UUUGCCAGAGUGAGACGUG 2177 CACGUCUCACUCUGGCAAA siRNA 1038 1038 UUGCCAGAGUGAGACGUGU 2178 ACACGUCUCACUCUGGCAA SIRNA 1039 1039 UGCCAGAGUGAGACGUGUG 2179 CACACGUCUCACUCUGGCA siRNA 1040 1040 GCCAGAGUGAGACGUGUGC 2180 GCACACGUCUCACUCUGGC SiRNA 1041 1041 CCAGAGUGAGACGUGUGCA 2181 UGCACACGUCUCACUCUGG siRNA 1042 1042 CAGAGUGAGACGUGUGCAG 2182 CUGCACACGUCUCACUCUG siRNA 1043 1043 AGAGUGAGACGUGUGCAGA 2183 UCUGCACACGUCUCACUCU siRNA 1044 1044 GAGUGAGACGUGUGCAGAA 2184 UUCUGCACACGUCUCACUC siRNA 1045 1045 AGUGAGACGUGUGCAGAAU 2185 AUUCUGCACACGUCUCACU siRNA 1046 1046 GUGAGACGUGUGCAGAAUG 2186 CAUUCUGCACACGUCUCAC siRNA 1047 1047 UGAGACGUGUGCAGAAUGA 2187 UCAUUCUGCACACGUCUCA siRNA 1048 1048 GAGACGUGUGCAGAAUGAA 2188 UUCAUUCUGCACACGUCUC siRNA 1049 1049 AGACGUGUGCAGAAUGAAC 2189 GUUCAUUCUGCACACGUCU siRNA 1050 1050 GACGUGUGCAGAAUGAACU 2190 AGUUCAUUCUGCACACGUC siRNA 1051 1051 ACGUGUGCAGAAUGAACUA 2191 UAGUUCAUUCUGCACACGU siRNA 1052 1052 CGUGUGCAGAAUGAACUAA 2192 UUAGUUCAUUCUGCACACG siRNA 1053 1053 GUGUGCAGAAUGAACUAAG 2193 CUUAGUUCAUUCUGCACAC siRNA 1054 1054 UGUGCAGAAUGAACUAAGC 2194 GCUUAGUUCAUUCUGCACA siRNA 1055 1055 GUGCAGAAUGAACUAAGCC 2195 GGCUUAGUUCAUUCUGCAC siRNA 1056 1056 UGCAGAAUGAACUAAGCCC 2196 GGGCUUAGUUCAUUCUGCA siRNA 1057 1057 GCAGAAUGAACUAAGCCCC 2197 GGGGCUUAGUUCAUUCUGC siRNA 1058 1058 CAGAAUGAACUAAGCCCCA 2198 UGGGGCUUAGUUCAUUCUG siRNA 1059 1059 AGAAUGAACUAAGCCCCAG 2199 CUGGGGCUUAGUUCAUUCU siRNA 1060 1060 GAAUGAACUAAGCCCCAGA 2200 UCUGGGGCUUAGUUCAUUC siRNA 1061 1061 AAUGAACUAAGCCCCAGAG 2201 CUCUGGGGCUUAGUUCAUU siRNA 1062 1062 AUGAACUAAGCCCCAGAGG 2202 CCUCUGGGGCUUAGUUCAU siRNA 1063 1063 UGAACUAAGCCCCAGAGGG 2203 CCCUCUGGGGCUUAGUUCA siRNA 1064 1064 GAACUAAGCCCCAGAGGGU 2204 ACCCUCUGGGGCUUAGUUC siRNA 1065 1065 AACUAAGCCCCAGAGGGUU 2205 AACCCUCUGGGGCUUAGUU siRNA 1066 1066 ACUAAGCCCCAGAGGGUUU 2206 AAACCCUCUGGGGCUUAGU siRNA 1067 1067 CUAAGCCCCAGAGGGUUUU 2207 AAAACCCUCUGGGGCUUAG siRNA 1068 1068 UAAGCCCCAGAGGGUUUUA 2208 UAAAACCCUCUGGGGCUUA siRNA 1069 1069 AAGCCCCAGAGGGUUUUAA 2209 UUAAAACCCUCUGGGGCUU siRNA 1070 1070 AGCCCCAGAGGGUUUUAAU 2210 AUUAAAACCCUCUGGGGCU siRNA 1071 1071 GCCCCAGAGGGUUUUAAUG 2211 CAUUAAAACCCUCUGGGGC siRNA 1072 1072 CCCCAGAGGGUUUUAAUGG 2212 CCAUUAAAACCCUCUGGGG siRNA 1073 1073 CCCAGAGGGUUUUAAUGGC 2213 GCCAUUAAAACCCUCUGGG siRNA 1074 1074 CCAGAGGGUUUUAAUGGCU 2214 AGCCAUUAAAACCCUCUGG siRNA 1075 1075 CAGAGGGUUUUAAUGGCUU 2215 AAGCCAUUAAAACCCUCUG siRNA 1076 1076 AGAGGGUUUUAAUGGCUUG 2216 CAAGCCAUUAAAACCCUCU siRNA 1077 1077 GAGGGUUUUAAUGGCUUGC 2217 GCAAGCCAUUAAAACCCUC siRNA 1078 1078 AGGGUUUUAAUGGCUUGCC 2218 GGCAAGCCAUUAAAACCCU siRNA 1079 1079 GGGUUUUAAUGGCUUGCCU 2219 AGGCAAGCCAUUAAAACCC siRNA 1080 1080 GGUUUUAAUGGCUUGCCUG 2220 CAGGCAAGCCAUUAAAACC siRNA 1081 1081 GUUUUAAUGGCUUGCCUGC 2221 GCAGGCAAGCCAUUAAAAC SiRNA 1082 1082 UUUUAAUGGCUUGCCUGCU 2222 AGCAGGCAAGCCAUUAAAA siRNA 1083 1083 UUUAAUGGCUUGCCUGCUG 2223 CAGCAGGCAAGCCAUUAAA siRNA 1084 1084 UUAAUGGCUUGCCUGCUGU 2224 ACAGCAGGCAAGCCAUUAA siRNA 1085 1085 UAAUGGCUUGCCUGCUGUU 2225 AACAGCAGGCAAGCCAUUA siRNA 1086 1086 AAUGGCUUGCCUGCUGUUU 2226 AAACAGCAGGCAAGCCAUU siRNA 1087 1087 AUGGCUUGCCUGCUGUUUC 2227 GAAACAGCAGGCAAGCCAU siRNA 1088 1088 UGGCUUGCCUGCUGUUUCC 2228 GGAAACAGCAGGCAAGCCA siRNA 1089 1089 GGCUUGCCUGCUGUUUCCC 2229 GGGAAACAGCAGGCAAGCC siRNA 1090 1090 GCUUGCCUGCUGUUUCCCA 2230 UGGGAAACAGCAGGCAAGC siRNA 1091 1091 CUUGCCUGCUGUUUCCCAC 2231 GUGGGAAACAGCAGGCAAG siRNA 1092 1092 UUGCCUGCUGUUUCCCACA 2232 UGUGGGAAACAGCAGGCAA siRNA 1093 1093 UGCCUGCUGUUUCCCACAU 2233 AUGUGGGAAACAGCAGGCA siRNA 1094 1094 GCCUGCUGUUUCCCACAUA 2234 UAUGUGGGAAACAGCAGGC siRNA 1095 1095 CCUGCUGUUUCCCACAUAA 2235 UUAUGUGGGAAACAGCAGG siRNA 1096 1096 CUGCUGUUUCCCACAUAAA 2236 UUUAUGUGGGAAACAGCAG siRNA 1097 1097 UGCUGUUUCCCACAUAAAC 2237 GUUUAUGUGGGAAACAGCA siRNA 1098 1098 GCUGUUUCCCACAUAAACU 2238 AGUUUAUGUGGGAAACAGC siRNA 1099 1099 CUGUUUCCCACAUAAACUA 2239 UAGUUUAUGUGGGAAACAG siRNA 1100 1100 UGUUUCCCACAUAAACUAC 2240 GUAGUUUAUGUGGGAAACA siRNA 1101 1101 GUUUCCCACAUAAACUACC 2241 GGUAGUUUAUGUGGGAAAC siRNA 1102 1102 UUUCCCACAUAAACUACCU 2242 AGGUAGUUUAUGUGGGAAA siRNA 1103 1103 UUCCCACAUAAACUACCUC 2243 GAGGUAGUUUAUGUGGGAA siRNA 1104 1104 UCCCACAUAAACUACCUCA 2244 UGAGGUAGUUUAUGUGGGA siRNA 1105 1105 CCCACAUAAACUACCUCAG 2245 CUGAGGUAGUUUAUGUGGG SiRNA 1106 1106 CCACAUAAACUACCUCAGG 2246 CCUGAGGUAGUUUAUGUGG siRNA 1107 1107 CACAUAAACUACCUCAGGA 2247 UCCUGAGGUAGUUUAUGUG siRNA 1108 1108 ACAUAAACUACCUCAGGAG 2248 CUCCUGAGGUAGUUUAUGU siRNA 1109 1109 CAUAAACUACCUCAGGAGU 2249 ACUCCUGAGGUAGUUUAUG siRNA 1110 1110 AUAAACUACCUCAGGAGUC 2250 GACUCCUGAGGUAGUUUAU siRNA 1111 1111 UAAACUACCUCAGGAGUCA 2251 UGACUCCUGAGGUAGUUUA SIRNA 1112 1112 AAACUACCUCAGGAGUCAC 2252 GUGACUCCUGAGGUAGUUU siRNA 1113 1113 AACUACCUCAGGAGUCACU 2253 AGUGACUCCUGAGGUAGUU siRNA 1114 1114 ACUACCUCAGGAGUCACUG 2254 CAGUGACUCCUGAGGUAGU siRNA 1115 1115 CUACCUCAGGAGUCACUGU 2255 ACAGUGACUCCUGAGGUAG siRNA 1116 1116 UACCUCAGGAGUCACUGUA 2256 UACAGUGACUCCUGAGGUA siRNA 1117 1117 ACCUCAGGAGUCACUGUAA 2257 UUACAGUGACUCCUGAGGU siRNA 1118 1118 CCUCAGGAGUCACUGUAAA 2258 UUUACAGUGACUCCUGAGG siRNA 1119 1119 CUCAGGAGUCACUGUAAAA 2259 UUUUACAGUGACUCCUGAG siRNA 1120 1120 UCAGGAGUCACUGUAAAAU 2260 AUUUUACAGUGACUCCUGA siRNA 1121 1121 CAGGAGUCACUGUAAAAUA 2261 UAUUUUACAGUGACUCCUG siRNA 1122 1122 AGGAGUCACUGUAAAAUAA 2262 UUAUUUUACAGUGACUCCU siRNA 1123 1123 GGAGUCACUGUAAAAUAAA 2263 UUUAUUUUACAGUGACUCC siRNA 1124 1124 GAGUCACUGUAAAAUAAAC 2264 GUUUAUUUUACAGUGACUC siRNA 1125 1125 AGUCACUGUAAAAUAAACU 2265 AGUUUAUUUUACAGUGACU siRNA 1126 1126 GUCACUGUAAAAUAAACUG 2266 CAGUUUAUUUUACAGUGAC siRNA 1127 1127 UCACUGUAAAAUAAACUGG 2267 CCAGUUUAUUUUACAGUGA siRNA 1128 1128 CACUGUAAAAUAAACUGGC 2268 GCCAGUUUAUUUUACAGUG siRNA 1129 1129 ACUGUAAAAUAAACUGGCC 2269 GGCCAGUUUAUUUUACAGU siRNA 1130 1130 CUGUAAAAUAAACUGGCCU 2270 AGGCCAGUUUAUUUUACAG siRNA 1131 1131 UGUAAAAUAAACUGGCCUU 2271 AAGGCCAGUUUAUUUUACA siRNA 1132 1132 GUAAAAUAAACUGGCCUUG 2272 CAAGGCCAGUUUAUUUUAC siRNA 1133 1133 UAAAAUAAACUGGCCUUGU 2273 ACAAGGCCAGUUUAUUUUA siRNA 1134 1134 AAAAUAAACUGGCCUUGUU 2274 AACAAGGCCAGUUUAUUUU siRNA 1135 1135 AAAUAAACUGGCCUUGUUG 2275 CAACAAGGCCAGUUUAUUU siRNA 1136 1136 AAUAAACUGGCCUUGUUGU 2276 ACAACAAGGCCAGUUUAUU siRNA 1137 1137 AUAAACUGGCCUUGUUGUC 2277 GACAACAAGGCCAGUUUAU siRNA 1138 1138 UAAACUGGCCUUGUUGUCU 2278 AGACAACAAGGCCAGUUUA siRNA 1139 1139 AAACUGGCCUUGUUGUCUU 2279 AAGACAACAAGGCCAGUUU siRNA 1140 1140 AACUGGCCUUGUUGUCUUA 2280 UAAGACAACAAGGCCAGUU

TABLE 103 Additional Sequences SEQ ID NO: 5′ to 3′ Sequence 2443 GGGGGGGGAGGGAGCGAGAGGAATCCGACCCTGTC TCAGCCCACAGCCTCCGAGGTCTCCAAGTAAAGGG AAGGATCTTTAGCTGCATTAGACTTCAAAGCGTTT AGACCAGTTTCTCCATCTTACGGAGCGGTGAACGG GCTCAGGAATGTGGAGCGTTTCCTGGCGTCAAGCA GGTCAAAGTCAGCGCTGCTTTTTTTACAGACACTG CTTTTCTTACAGTCTTCGACTATAAACTCTACAAG AATAGGAATCTTCGTATTTTTTTCCTCTGCTGAAT TCCTAGTGCCCAGATTAGTGCTTGGCACATGATTA TAAGCGCCATGGCTATGGCTAGTGTTAAATTGCTT GCCGGTGTTTTAAGAAAGCCAGATGCCTGGATTGG ACTCTGGGGTGTTCTCCGAGGGACACCTTCATCAT ACAAACTCTGTACTTCCTGGAATCGATACTTGTAT TTTTCTAGTACCAAGTTACGTGCACCAAATTATAA AACACTTTTTTATAATATTTTCTCACTGAGACTCC CAGGGCTTTTACTATCTCCAGAATGTATTTTTCCT TTTTCCGTAAGACTCAAAAGTAATATAAGGTCTAC AAAATCTACTAAAAAGTCTCTGCAAAAAGTAGATG AAGAGGACTCTGATGAAGAAAGCCATCATGATGAG ATGAGTGAGCAGGAAGAGGAGCTTGAGGATGATCC TACTGTAGTCAAAAACTATAAAGACCTGGAAAAAG CAGTTCAGTCTTTTCGGTATGATGTTGTCCTGAAG ACGGGGCTAGATATTGGGAGAAACAAAGTGGAAGA TGCTTTCTACAAAGGTGAACTCAGGCTGAATGAGG AAAAATTATGGAAGAAAAGCAGAACGGTGAAAGTG GGAGATACATTGGATCTTCTCATTGGAGAGGATAA AGAAGCAGGAACAGAGACAGTTATGCGGATTCTCT TGAAAAAAGTGTTTGAAGAGAAGACTGAAAGTGAA AAATACAGAGTGGTGTTACGGCGGTGGAAAAGTTT AAAGTTGCCTAAGAAGAGAATGTCTAAATAAATGG ATTGCTTTTTAGCAATAGAGCTGCTTTCTAGTGGT AAAGGAAGGGGTCACCTGAAAAATAGGACATTTTT ATTAAAATAAAGTTCTCTTAGCGTT 2462 GGGGTGGGGAGGGAGCGAGAGGAATCCGACCCTGT CTCAGCCCACAGCCTCCGAGGTCTCCAAGTAAAGG GAAGGATCTTTAGCTGCATTAGACTTCAAAGCGTT TAGACCAGTTTCTCCATCTTACGGAGCGGTGAACG GGCTCAGGAATGTGGAGCGTTTCCTGGCGTCAAGC AGGTCAAAGTCAGCGCTGCTTTTTTTACAGACACT GCTTTTCTTACAGTCTTCGACTATAAACTCTACAA GAATAGGAATCTTCGTATTTTTTTCCTCTGCTGAA TTCCTAGTGCCCAGATTAGTGCTTGGCACATGATT ATAAGCGCCATGGCTATGGCTAGTGTTAAATTGCT TGCCGGTGTTTTAAGAAAGCCAGATGCCTGGATTG GACTCTGGGGTGTTCTCCGAGGGACACCTTCATCA TACAAACTCTGTACTTCCTGGAATCGATACTTGTA TTTTTCTAGTACCAAGTTACGTGCACCAAATTATA AAACACTTTTTTATAATATTTTCTCACTGAGACTC CCAGGGCTTTTACTATCTCCAGAATGTATTTTTCC TTTTTCCGTAAGACTCAAAAGTAATATAAGGTCTA CAAAATCTACTAAAAAGTCTCTGCAAAAAGTAGAT GAAGAGGACTCTGATGAAGAAAGCCATCATGATGA GATGAGTGAGCAGGAAGAGGAGCTTGAGGATGATC CTACTGTAGTCAAAAACTATAAAGACCTGGAAAAA GCAGTTCAGTCTTTTCGGTATGATGTTGTCCTGAA GACGGGGCTAGATATTGGGAGAAACAAAGTGGAAG ATGCTTTCTACAAAGGTGAACTCAGGCTGAATGAG GAAAAATTATGGAAGAAAAGCAGAACGGTGAAAGT GGGAGATACATTGGATCTTCTCATTGGAGAGGATA AAGAAGCAGGAACAGAGACAGTTATGCGGATTCTC TTGAAAAAAGTGTTTGAAGAGAAGACTGAAAGTGA AAAATACAGAGTGGTGTTACGGCGGTGGAAAAGTT TAAAGTTGCCTAAGAAGAGAATGTCTAAATAAATG GATTGCTTTTTAGCAATAGAGCTGCTTTCTAGTGG TAAAGGAAGGGGTCACCTGAAAAATAGGACATTTT TATTAAAATAAAGTTCTCTTAGCGTT